DiseaseLand Summary

From Array Suite Wiki

Revision as of 10:52, 2 September 2016 by LeiShang (Talk | contribs)
Jump to: navigation, search


Contents

Introduction

Disease areas

We have processed various publically available projects for DiseaseLand and separated them into two major categories: ImmunoLand and CVMLand. The main disease areas are as follows for each Land:

ImmunoLand
* Arthritis
* Asthma/Allergy
* IBD (Crohn Disease, Ulcerative Colitis)
* Infectious diseases 
* Lung disease (COPD, Pulmonary Fibrosis)
* Multiple Sclerosis
* Neurodegenerative disease (Alzheimer’s, Parkinson’s, ALS)
* Psoriasis and other skin disease 
* SLE (Systemic Lupus Erythematosus)

CVMLand
* Cardiovascular disease
* Kidney disease (Chronic Kidney disease, Polycystic Kidney disease, Diabetic Nephropathy)
* Diabetes (Type I and Type II)
* Fatty Liver disease
* Obesity

Data Sources

We select public projects from GEO, ArrayExpress, dbGAP, and other large data repositories like BluePrint, GTEx, ImmGen. Customers can also deposit their own in-house data into Land.

Land Summary

The total number of projects, samples and comparisons for supported organisms are listed in the table as below

Items DiseaseHuman DiseaseMouse
Projects 2016Q2 950 515
# Samples 2016Q2 60272 15855
# Comparison 2016Q2 2870 1767

Project Summary

The project-level summary is listed in the table as below. Each column is sortable alphabetically.

Project Collection DiseaseGroup # of Samples # of Comparisons Description
GSE10006 ImmunoHuman COPD 87 6 Lectins are proteins present on cell surfaces or as shed extracellular proteins that function in innate immune defense as phagocytic receptors to recognize specific bacterial cell wall components. Based on the knowledge that cigarette smoking is associated with increased risk of bacterial infection, we hypothesized that cigarette smoking may modulate the expression of lectin genes in the airway epithelium. Affymetrix HG U133 Plus 2.0 microarrays were used to survey expression of lectin genes in large (3rd to 4th order bronchi) airway epithelium from 9 normal nonsmokers and 20 phenotypic normal smokers and small (10th to 12th order bronchi) airway epithelium from 13 normal nonsmokers and 20 phenotypic normal smokers. From the 72 lectin genes that were surveyed, there were no changes (>2-fold change, p<0.05) in gene expression in either large or small airway epithelium among normal smokers compared to nonsmokers except for a striking down regulation in both large and small airway epithelium of normal smokers of intelectin 1, a recently described lectin that participates in the innate immune response by recognizing and binding to galactofuranosyl residues in the cell walls of bacteria (large airway epithelium, p<0.003; small airway epithelium, p<0.002). TaqMan RT-PCR confirmed the observation that intelectin 1 was down-regulated in both large (p<0.05) and small airway epithelium (p<0.02) of normal smokers compared to normal nonsmokers. Immunohistochemistry assessment of biopsies of the large airway epithelium of normal nonsmokers demonstrated intelectin 1 was expressed in secretory cells, with qualitatively decreased expression in biopsies from normal smokers. Western analysis confirmed the decreased expression of intelectin 1 in airway epithelium of normal smokers compared to normal nonsmokers (p<0.02). Finally, compared to normal nonsmokers, intelectin 1 expression was decreased in small airway epithelium of smokers with early COPD (n= 13, p<0.001) and smokers with established COPD (n= 14, p<0.001), in a fashion similar to that of normal smokers. In the context that intelectin 1 is an epithelial molecule that likely plays a role in defense against bacteria, the down regulation of expression of intelectin 1 in response to cigarette smoking may contribute to the increase in susceptibility to infections observed in smokers, including those with COPD.
GSE10024 ImmunoHuman Arthritis 6 2 We have studied the expression profile of 3D cultured human chondrocytes that were stimulated with supernatant of synovial fibroblasts derived from a RA patient (RASF=HSE cell line) and from a normal donor (NDSF=K4IM cell line), respectively. For this purpose, passage 2 human chondrocytes were cultured for 14 days in alginate beads and subsequently stimulated for 48 hours with supernatant of RASF and NDSF. Baseline expression was determined of unstimulated chondrocytes. Differential genome-wide microarray analysis of RASF and NDSF stimulated chondrocytes disclosed a distinct expression profile related to cartilage destruction involving marker genes of inflammation (COX-2), NF-kappa B signaling pathway (TLR2), cytokines/chemokines and receptors (CXCL1-3, CCL20, CXCL8, CXCR4, IL-6, IL-1beta), matrix degradation (MMP-10, MMP-12) and suppressed matrix synthesis (COMP). Thus, transcriptome profiling of RASF and NDSF stimulated chondrocytes revealed a disturbed catabolic-anabolic homeostasis of chondrocyte function. This study provides a comprehensive insight into the molecular regulatory processes induced in human chondrocytes during RA-related cartilage destruction.
GSE10038 ImmunoHuman COPD 11 0 HIV1+ smokers develop emphysema at an earlier age and with a higher incidence than HIV1- smokers. Based on the knowledge that human alveolar macrophages (AM) are capable of producing proteases that degrade extracellular matrix components, we hypothesized that upregulation of AM matrix metalloproteinases may be associated with the emphysema of HIV1+ smokers. To test this hypothesis, microarray analysis was used to screen which MMP genes were expressed by AM isolated by bronchoalveolar lavage (BAL) of HIV1+ smokers with early emphysema. For each of the MMP genes observed to be expressed (MMP-1, -2, -7, -9, -10, -12 and -14), TaqMan PCR was used to quantify the relative expression in AM from 4 groups of individuals: HIV1 healthy nonsmokers, HIV1- healthy smokers, HIV1- smokers with early emphysema and HIV1+ smokers with early emphysema. Strikingly, while AM gene expression of MMPs was higher in HIV1- individuals with emphysema in comparison with HIV1- healthy smokers, for the majority of the MMPs (-1, -7, -9, -10, -12), AM expression from HIV1+ smokers with early emphysema was significantly higher than HIV1- smokers with early emphysema. Consistent with these observations, HIV1+ individuals with early emphysema had higher levels of epithelial lining fluid MMPs (-2, -7, -9,-12) than the 3 HIV1 groups. Interestingly, the active forms of MMP-2, -9 and -12 were detected in epithelial lining fluid from HIV1+ individuals with early emphysema, but not in any of the other groups. Considering that the substrate specificity of the upregulated AM MMPs includes collagenases, gelatinases, matrilysins and elastase, these data suggest that upregulated AM MMP genes and activation of MMP proteins may contribute to the emphysema of HIV1+ individuals who smoke.
GSE10080 ImmunoHuman 2015Q2 12 1 Cryopreserved human PBMCs from six donors were stimulated with anti-CD3/CD28 beads in the presence or absence of 100ng/ml IL-23 for 22 hours. RNA samples were assessed for consistency with a Bioanalyzer (Agilent) and quantified by a Nanodrop® ND 1000 Spectrophotometer (Nanodrop Technologies, USA). Expression array data was quantile normalised, detection above background statistical testing performed, comparison between activated un-stimulated versus activated IL-23 stimulated conditions performed as a paired test using the Illumina Custom differential expression algorithm (all implemented in Illumina BeadStudio GeneExpression Module v3.2).\r\nTwo sample groups were compared, each with 6 biological replicates. Group 1 was stimulated with CD3CD28 antibody coated beads as a control group for 22hours. Group 2 was stimulated as the control group and treated with IL-23 100ng/ml for the same time period.
GSE10135 ImmunoHuman COPD 92 3 Smokers weigh less and have less body fat than non-smokers, and increased body fat and weight gain are observed following smoking cessation. To assess a possible molecular mechanism underlying the inverse association between smoking and body weight, we hypothesized that smoking may induce the expression of a fat depleting gene in the airway epithelium, the cell population that takes the brunt of the stress of cigarette smoke. As a candidate gene we evaluated the expression of alpha2-zinc-glycoprotein1 (AZGP1), a soluble protein that stimulates lipolysis, induces a reduction in body fat in mice and is associated with the cachexia related to cancer, and is known to be expressed in secretory cells of lung epithelium. To assess if smoking upregulates AZGP1 expression, microarray analysis with TaqMan confirmation was used to evaluate large airway epithelial samples obtained by fiberoptic bronchoscopy from 37 normal smokers and 55 normal nonsmokers. Both microarray and TaqMan analysis demonstrated that AZGP1 mRNA levels were higher in the large airway epithelium of normal smokers compared to normal nonsmokers (p<0.05, all comparisons). Western analysis of airway biopsies of smokers compared with nonsmokers demonstrated upregulation of AZGP1 at the protein level, and immunohistochemical analysis demonstrated upregulation of AZGP1 in secretory as well as neuroendocrine cells of smokers. In the context that AZGP1 is involved in lipolysis and fat loss, its overexpression in the airway epithelium of chronic smokers may represent one mechanism for the weight difference in smokers vs nonsmokers.
GSE10191 ImmunoHuman IBD 23 2 Activation of inflammatory pathways in human IBD. Leukocyte recruitment pathways including those for eosiniphils are activated in the affected colon in IBD. However, the functional implications of this are not known. We hypothesized that pro-inflammatory eotaxin (CCL11) dependent networks would be up regulated in the colon of pediatric patients with Ulcerative Colitis (UC), and that these would regulate eosinophil recruitment to the gut. These experiments tested differential colon gene expression relative to these pathways in healthy and UC samples. Colon biopsy samples were obtained from UC patients at diagnosis, and healthy controls. The global pattern of gene expression was determined using GeneSpring software, and biological networks were identified using Ingenuity software. Data suggested that a leukocyte recruitment network which includeds CCL11 is up regulated in pediatric UC at diagnosis. The degree of up regulation of these genes compared to healthy controls was remarkably conserved within the UC patient group, suggesting common mechanisms of mucosal inflammation.\r\nThese experiments tested differential colon gene expression relative to these pathways in healthy and UC samples.
GSE10311 ImmunoHuman Osteoporosis 21 4 Osteoblasts are key players in bone remodeling. The accessibility of human primary osteoblast-like cells (HOb) from bone explants render them a lucrative model for studying molecular physiology of bone turnover, discovery of novel anabolic therapeutics and mesenchymal cell biology in general. Relatively little is known about resting and dynamic expression profiles of HObs and no studies have been conducted to date to systematically assess the osteoblast transcriptome. The aim of this study was to characterize HObs and investigate signaling cascades and gene networks using genomewide expression profiling in resting and Bone Morphogenic Protein (BMP)-2 and Dexamethasone induced cells.\r\nOur data showed a vast number of genes and networks expressed predominantly in HObs as compared to closely related cells such as fibroblasts or chondrocytes. For instance, genes in the insulin-like growth factor (IGF) signaling pathway were enriched in HObs (p=0.003) and included the binding proteins (IGFBP1, 2, 5) and IGF-2 and its receptor. Another HOb specific expression pattern included leptin and its receptor (p<10-8). Furthermore, after stimulating HObs with Dexamethasone or BMP-2, the expression of several interesting genes and pathways were observed where data supported the role of peripheral leptin signaling in bone cell function.\r\nIn conclusion, we provide the landscape of tissue-specific and dynamic gene expression in HObs, a resource, which will allow utilization of osteoblasts as a model to study specific gene networks and gene families related to human bone physiology and diseases.
GSE10325 ImmunoHuman SLE 67 3 Gene expression profile studies have identified an interferon signature in whole blood or mononuclear cell samples from patients with systemic lupus erythematosus. This study was designed to determine whether specific lymphocyte and myeloid subsets freshly isolated from the blood of systemic lupus erythematosus patients demonstrated unique gene expression profiles compared to subsets isolated from healthy controls.
GSE10500 ImmunoHuman Arthritis 8 1 Macrophages from RA synovial fluids were compared to primary human blood-derived macrophages.
GSE10575 ImmunoHuman Arthritis 12 1 The regeneration of diseased hyaline cartilage remains a great challenge, mainly because degeneration activities after major injury or due to age-related processes overwhelm the self-renewal capacity of the tissue. We show that repair tissue from human articular cartilage of late stages of osteoarthritis harbor a unique progenitor cell population, termed chondrogenic progenitor cells exhibiting stem cell characteristics, such as multipotency, lack of immune system activation and, in particular, migratory activity. The isolated CPC exhibit a high chondrogenic potential and were able to populate diseased tissue in vivo. Moreover, down-regulation of the osteogenic transcription factor runx-2 enhanced the expression of the chondrogenic transcription factor sox-9 and consequently the matrix synthesis potential of chondrogenic progenitor cells. Our results, while offering new insight into the biology of progenitor cells from diseased cartilage tissue, might assist future strategies to treat late stages of osteoarthritis.
GSE10616 ImmunoHuman IBD 58 2 Colon gene expression in human IBD. The three major clinical subsets of Inflammatory Bowel Disease (IBD) include colon-only Crohn's Disease (CD), ileo-colonic CD, and Ulcerative Colitis (UC). These experiments tested differential colon gene expression in these three types of IBD, relative to healthy control samples, and the local degree of mucosal inflammation as measured by the CD Histological Index of Severity (CDHIS). Colon biopsy samples were obtained from IBD patients at diagnosis and during therapy, and healthy controls. The global pattern of gene expression was determined using GeneSpring software, with a focus upon candidate genes identified in a recent genome wide association study in pediatric onset IBD. Data suggested that two of these candidate genes are up regulated in pediatric IBD, partially influenced by local mucosal inflammation.\r\nThese experiments tested differential colon gene expression in healthy, CD, and UC samples for candidate genes identified in a recent pediatric onset IBD genome wide association study.
GSE10667 ImmunoHuman PulmonaryFibrosis 46 2 Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disease associated with significant morbidity and mortality. We identified a combinatorial signature of 5 proteins that was sufficient to distinguish IPF patients from controls; of these proteins MMP7 and MMP1 exhibited significantly higher values in both peripheral blood concentrations and lung tissue gene expression, suggesting their role as true biomarkers.
GSE10867 ImmunoHuman nomodel 18 0 Background and aims: Dysregulation of intestinal epithelial cells performance associates with an array of pathologies whose onset mechanisms are incompletely understood. The aim of the present study was to provide a map of gene expresssion patterns along the human healthy adult gastro-intestinal tract and to implement a new procedure for microarray data noise filtering that would allow their use as a reference when screening for pathological deviations, such as inflammatory bowel disease (IBD). Methods: Gene expression profiles in antrum, duodenum, jejunum, ileum and transverse colon biopsies were measured with the Affymetrix U133A array and principal component analysis was used to identify region-selective biomarkers. These data were intersected with highly variable genes from a public dataset of gene expression in the ileal and colonic healthy regions of UC and Crohn’s disease patients. Moreover, gene sets covering gut functions not entirely accounted for by the available public tools were constructed to monitor their expression along the GI tract. Results: 166 genes were found to be responsible for distinguishing the five regions considered. Fourteen had never been described in the GI tract, including a semaphorin probably implicated in pathogen invasion, and six other novel genes. Similar analysis of the IBD datasets revealed that samples stratify based on disease rather than on the intestinal region. This withstanding, eleven genes were identified as possible early predictors of Crohn’s and/or UC in ileum and/or colon. These include CLCA4 and SLC26A2, both implicated in ion transport. Conclusions: This novel approach, validated by retrieving known gene profiles, allowed the identification of promising new leads both in health and IBD state.
GSE10896 ImmunoHuman COPD 24 6 Oxidative stress as a result of cigarette smoking is an important etiological factor in the pathogenesis of chronic obstructive pulmonary disease (COPD), a chronic steroid-insensitive inflammatory disease of the airways. The activity of the transcriptional co-repressor Histone deacetylase-2 (HDAC2) is dramatically reduced in COPD and cells exposed to oxidative stress or cigarette smoke. Moreover, curcumin (diferuloylmethane), a dietary polyphenol, at concentrations upto 1uM specifically restores cigarette smoke extract (CSE)- or oxidative stress- impaired HDAC2 activity. The aim of this study was to therefore identify any links through those gene sets that are affected by oxidative stress and subsequent treatment with curcumin in order to determine whether or not this could explain the impact of curcumin on restoration of oxidant impaired HDAC2 transcriptional co-repressor activity.
GSE11057 ImmunoHuman SLE 17 2 Microarray deconvolution is a technique for quantifying the relative abundance of constituent cells in a mixture based on that mixture's microarray signature and the signatures of the purified constituents. It has been applied to yeast and other systems but not to blood samples.\r\nHere we test the ability of this technique to determine the fractions of subsets of memory T cells in peripheral blood mononuclear cell (PBMC) samples.
GSE11058 ImmunoHuman nomodel 24 0 Microarray deconvolution is a technique for quantifying the relative abundance of constituent cells in a mixture based on that mixture's microarray signature and the signatures of the purified constituents. Its ability to discriminate related human cells is unknown.\r\nHere we test the ability of this technique to determine the fractions of transformed cells of immune origin in mixed samples.
GSE11083 ImmunoHuman Arthritis 83 4 Total RNA from peripheral blood mononuclear cells (PBMC) and neutrophils from children with juvenile dermatomyositis (JDM) and juvenile idiopathic arthritis (JIA) were separately compared to pediatric control samples.
GSE11196 ImmunoHuman PulmonaryFibrosis 48 4 As a group, fibroproliferative disorders of the lung, liver, kidney, heart, vasculature and integument are common, progressive and refractory to therapy. They can emerge following toxic insults, but are frequently idiopathic. Their enigmatic propensity to resist therapy and progress to organ failure has focused attention on the myofibroblast – the primary effector of the fibroproliferative response. A central unanswered question is whether these myofibroblasts have acquired a distinct pathological phenotype - or whether they are normal myofibroblasts with a pathological phenotype that depends upon residing in a sea of pro-fibrotic cytokines and an abnormal extracellular matrix.\r\nUsing a systems approach to study this question in a prototype fibrotic disease, Idiopathic Pulmonary Fibrosis (IPF); here we show organized changes in the gene expression pathway of primary lung myofibroblasts that persist for up to 9 sub-cultivations in vitro. When comparing IPF and control myofibroblasts in a 3-dimensional type I collagen matrix, more genes differed at the level of ribosome recruitment than at the level of transcript abundance, indicating pathological translational control as a major characteristic of IPF myofibroblasts. To determine the effect of matrix state on translational control, myofibroblasts were permitted to contract the matrix. Ribosome recruitment in control myofibroblasts was relatively stable. In contrast, IPF cells manifested large alterations in the ribosome recruitment pattern. Pathological studies suggest an epithelial origin for IPF myofibroblasts through the epithelial to mesenchymal transition (EMT). In accord with this, we found systems-level indications for TGF-beta -driven EMT as one source of IPF myofibroblasts.
GSE1122 ImmunoHuman COPD 15 2 Gene expression profiling of lung tissue from undiseased (NML), 'usual' emphysema (EML), and Alpha-1 Antitrypsin Deficiency-related emphysema (ADL).
GSE11292 ImmunoHuman NormalControl 81 37 Human FOXP3+CD25+CD4+ regulatory T cells (Tregs) play a dominant role in the maintenance of immune homeostasis. Several genes are known to be important for murine Tregs, but for human Tregs the genes and underlying molecular networks controlling the suppressor function still largely remain unclear. We here performed a high-time-resolution dynamic analysis of the transcriptome during the very early phase of human Treg/ CD4+ T-effector cell activation. After constructing a correlation network specific for Tregs based on these dynamic data, we described a strategy to identify key genes by directly analyzing the constructed undirected correlation network. Six out of the top 10 ranked key hubs are known to be important for Treg function or involved in autoimmune diseases. Surprisingly, PLAU (the plasminogen activator urokinase) was among the 4 new key hubs. We here show that PLAU was critical for expression regulation of FOXP3, EOS and several other important Treg genes and the suppressor function of human Tregs. Moreover, we found Plau inhibits murine Treg development and but promotes the suppressive function. Further analysis unveils that PLAU is particularly important for memory Tregs and that PLAU mediates Treg suppressor function via STAT5 and ERK signaling pathways. Our study shows the potential for identifying novel key genes for complex dynamic biological processes using a network strategy based on high-time-resolution data, and highlights a critical role of PLAU in both human and murine Tregs. The construction of a dynamic correlation network of human Tregs provides a useful resource for the understanding of Treg function and human autoimmune diseases.\r\nThe high-time-resolution time-series transcriptomic data during the very early phase of human Treg/Teff activation could be generally used for further mechanistic analysis of human Treg function. These data could be further used for biological network analysis, dynamic analysis, modeling by experimental researchers, bioinformaticians, computational biologists and systems biologists.
GSE1141 ImmunoHuman IBD 6 0 Samples for microarray analysis were derived from terminal ileum and colonic tissues from probands with Crohn´s disease and Ulcerative Colitis and control patients, respectively. IBD tissue biopsies from non-inflamed regions 10 cm distant from pathological areas were selected. To minimize inter-individual differences in gene expression and to enrich for IBD-specific transcriptional events, 2.5 µg of total RNA from terminal ileum and colon transversum from four individuals of each patient and control group were used for pooling. Gene expression profiles were determined using Affymetrix HG-U133A Gene Chips.
GSE1142 ImmunoHuman IBD 6 0 Samples for microarray analysis were derived from terminal ileum and colonic tissues from probands with Crohn´s disease and Ulcerative Colitis and control patients, respectively. IBD tissue biopsies from non-inflamed regions 10 cm distant from pathological areas were selected. To minimize inter-individual differences in gene expression and to enrich for IBD-specific transcriptional events, 2.5 µg of total RNA from terminal ileum and colon transversum from four individuals of each patient and control group were used for pooling. Gene expression profiles were determined using Affymetrix HG-U133B Gene Chips.
GSE11499 ImmunoHuman IBD 11 1 The whole-genome oligonucleotide microarray analysis of peripheral blood samples can contribute to the determination of distant blood markers of local pathophysiological alterations in colorectal diseases. These markers can lead to alternative screening procedures.
GSE11501 ImmunoHuman BI Rush 132 1 The goal of this study was to study the effect of genetic variation on gene expression of untouched primary leucocytes. This expression data is used in conjunction with genome-wide association genotype data that is available for the celiac disease samples, typed on the Illumina Infinium HumanHap300 platform.\r\nAll genotype data are available upon request.
GSE1152 ImmunoHuman IBD 12 0 Samples for microarray analysis were derived from terminal ileum and colonic tissues from probands with Crohn´s disease and Ulcerative Colitis and control patients, respectively. IBD tissue biopsies from non-inflamed regions 10 cm distant from pathological areas were selected. To minimize inter-individual differences in gene expression and to enrich for IBD-specific transcriptional events, 2.5 µg of total RNA from terminal ileum and colon transversum from four individuals of each patient and control group were used for pooling.
GSE11784 ImmunoHuman COPD 171 2 The first changes associated with smoking are in the small airway epithelium (SAE). Given that smoking alters SAE gene expression, but only a fraction of smokers develop chronic obstructive pulmonary disease (COPD), we hypothesized that assessment of SAE genome-wide gene expression would permit biologic phenotyping of the smoking response, and that a subset of healthy smokers would have a “COPD-like” SAE transcriptome. SAE (10th-12th generation) was obtained via bronchoscopy of healthy nonsmokers, healthy smokers and COPD smokers and microarray analysis was used to identify differentially expressed genes. Individual responsiveness to smoking was quantified with an index representing the % of smoking-responsive genes abnormally expressed (ISAE), with healthy smokers grouped into “high” and “low” responders based on the proportion of smoking-responsive genes up- or down-regulated in each smoker. Smokers demonstrated significant variability in SAE transcriptome with ISAE ranging from 2.9 to 51.5%. While the SAE transcriptome of “low” responder healthy smokers differed from both “high” responders and smokers with COPD, the transcriptome of the “high” responder healthy smokers was indistinguishable from COPD smokers. The SAE transcriptome can be used to classify clinically healthy smokers into subgroups with lesser and greater responses to cigarette smoking, even though these subgroups are indistinguishable by clinical criteria. This identifies a group of smokers with a “COPD-like” SAE transcriptome.
GSE11886 ImmunoHuman Psoriasis 33 4 OBJECTIVE: To determine whether macrophages, a type of cell implicated in the pathogenesis of ankylosing spondylitis (AS), exhibit a characteristic gene expression pattern. METHODS: Macrophages were derived from the peripheral blood of 8 AS patients (median disease duration 13 years [range <1-43 years]) and 9 healthy control subjects over 7 days with the use of granulocyte-macrophage colony-stimulating factor. Cells were stimulated for 24 hours with interferon-gamma (IFNgamma; 100 units/ml), were left untreated for 24 hours, or were treated for 3 hours with lipopolysaccharide (LPS; 10 ng/ml). RNA was isolated and examined by microarray and real-time quantitative reverse transcription-polymerase chain reaction analysis. RESULTS: Microarray analysis revealed 198 probe sets detecting the differential expression of 141 unique genes in untreated macrophages from AS patients compared with healthy controls. Clustering and principal components analysis clearly distinguished AS patients and controls. Of the differentially expressed genes, 78 (55%) were IFN-regulated, and their relative expression indicated a reverse IFN signature in AS patient macrophages, where IFNgamma-up-regulated genes were underexpressed and down-regulated genes were overexpressed. Treatment of macrophages with exogenous IFNgamma normalized the expression of these genes between patients and controls. In addition, the messenger RNA encoded by the IFNgamma gene was approximately 2-fold lower in AS patient macrophages at baseline (P = 0.004) and was poorly responsive to LPS (P = 0.018), as compared with healthy controls. CONCLUSIONS: Our findings reveal consistent differences in gene expression in macrophages from AS patients, with evidence of a striking reverse IFN signature. Together with poor expression and responsiveness of the IFNgamma gene, these results suggest that there may be a relative defect in IFNgamma gene regulation, with autocrine consequences and implications for disease pathogenesis.
GSE11903 ImmunoHuman Psoriasis 89 7 The success of TNF inhibitors for treatment of psoriasis and other inflammatory diseases was previously attributed to blockade of innate immunity. In a clinical trial using etanercept TNF blocking agent to treat psoriasis vulgaris, we used affymetrix gene arrays to analyze broad gene profiles in lesional skin at multiple timepoints during drug treatment (baseline, and weeks 1, 2, 4 and 12) compared to non-lesional skin. This analysis created a temporal model of TNF-dependent gene regulation that informs molecular mechanisms of TNF-mediated inflammation. We identified four gene clusters that were differentially down-modulated during etanercept treatment: the cluster down-regulated most rapidly contained mostly dendritic cell activation genes. Culturing human keratinocytes with TNF, IFNg and IL-17 generated a list of keratinocyte genes regulated by each cytokine. The IL-17 pathway genes were strongly down-modulated early, whereas IFNg pathway genes were not down-modulated until final disease resolution at week 12. Finally, we show that TNF blockade rapidly inhibits IL-12/IL-23 p40 subunit expression, and that p40 neutralization inhibits psoriatic dermal émigré-mediated Th17 polarization. We hypothesize that etanercept inhibits myeloid dendritic cell production of IL-23, a Th17 survival cytokine, resulting in rapid downregulation of IL-17 pathway genes. This data links effects of TNF blockade on the innate immune system with the adaptive immune system.
GSE11906 ImmunoHuman COPD 221 7 Microarray technology provides a powerful tool for defining gene expression profiles of airway epithelium that lend insight into the pathogenesis of human airway disorders. The focus of this study was to establish rigorous quality control parameters to ensure that microarray assessment of the airway epithelium is not confounded by experimental artifact. Samples (total n=223) of trachea, large and small airway epithelium were collected by fiberoptic bronchoscopy of 144 individuals (42 healthy non-smokers, 49 healthy smokers, 11 symptomatic smokers, 22 smokers with lone emphysema with normal spirometry, and 20 smokers with COPD) were processed and hybridized to Affymetrix HG-U133 2.0 Plus microarrays. The pre- and post-chip quality control (QC) criteria established, included: (1) RNA quality, assessed by RNA Integrity Number (RIN) =7.0 using Agilent 2100 Bioanalyzer software; (2) cRNA transcript integrity, assessed by signal intensity ratio of GAPDH 3' to 5' probe sets =3.0; and (3) the multi-chip normalization scaling factor =10.0\r\nOf the 223 samples, 213 (95.5%) passed the QC criteria. In a data set of 34 arrays (10 samples failing QC criteria, 24 randomly chosen samples passing QC criteria), correlation coefficients for pairwise comparisons of expression levels for 100 housekeeping genes in which at least one array failed the QC criteria were significantly lower (average Pearson r = 0.90 ± 0.04) and more broadly dispersed than correlation coefficients for pairwise comparisons between any two arrays that passed the QC criteria (average Pearson r = 0.97 ± 0.01). By using the QC cutoff criteria, the inter-array variability, as assessed by the coefficient of variation in the expression levels for 100 housekeeping genes, was reduced from 35.7% to 21.7%. Based on the aberrant housekeeping gene data generated from samples failing the established QC criteria, we propose that the QC criteria outlined in this study can accurately distinguish high quality from low quality data and can be used to delete poor quality microarray samples before proceeding to higher-order biological analyses and interpretation.
GSE11908 ImmunoHuman nomodel 412 0 We designed a strategy for microarray analysis that is based on the identification of transcriptional modules formed by genes coordinately expressed in multiple disease data sets. Mapping changes in gene expression at the module level generated disease-specific transcriptional fingerprints that provide a stable framework for the visualization and functional interpretation of microarray data.
GSE11909 ImmunoHuman SLE 173 2 Transcriptional modules were used as a basis for the selection of biomarkers and the development of a multivariate transcriptional indicator of disease progression in patients with systemic lupus erythematosus.
GSE11952 ImmunoHuman COPD 83 1 Nuclear factor erythroid 2-related factor 2 (NFE2L2, Nrf2) is an oxidant responsive transcription factor known to induce phase 2 detoxifying and antioxidant genes to protect cells from oxidative stress. Cigarette smoke, with its large oxidant content, is a major stressor to the small airway epithelium, the cells of which are vulnerable to oxidant damage and consequent malignant transformation. In this study, we assessed the role of cigarette smoke in activation of Nrf2 in the human small airway epithelium in vivo. Fiberoptic bronchoscopy was used to sample a pure population of small airway epithelium in 38 healthy nonsmokers and 45 healthy smokers, and gene expression was assessed using Affymetrix HG-U133 Plus 2.0 microarrays. Compared to that of healthy nonsmokers, Nrf2 protein was significantly activated in the small airway epithelium of healthy normal smokers and localized in the nucleus (p<0.05). Of the human homologs of 201 known murine Nrf2-mediated genes, 13 highly smoking-responsive genes were identified (p<10-4, all comparisons smokers to nonsmokers). Using a “Nrf2-index” to quantify the extent of expression in the small airway epithelium of these 13 known Nrf2 genes, variability in the level of expression was observed among the 45 healthy smokers, but the variability was coordinately modulated among the 13 genes, an observation confirmed by TaqMan quantitative PCR. This variability in the coordinate level of expression of the 13 Nrf2-mediated genes was independent of the smoking history. Based on these observations, the “Nrf2 index” was used to evaluate whether other genes modulated by smoking in the small airway epithelium were also coordinately up- or down- modulated among the 45 healthy smokers. Two genes, pirin (PIR) and UDP glucuronosyltransferase 1 family polypeptide A4 (UGT1A4), not previously known to be modulated by Nrf2 were identified as being coordinately modulated among the 45 smokers. Both genes contain several functional antioxidant response elements in the promoter region. Using an electrophoretic mobility shift assay, these antioxidant response elements in the promoters of PIR and UGT1A4 responded in vitro to activated Nrf2. These observations are consistent with the concept that Nrf2 plays an important role in regulating cellular defenses against smoking in the highly vulnerable small airway epithelium cell population, and that there is variability among the population in the relative Nrf2 responsiveness to a similar oxidant burden.
GSE12021 ImmunoHuman Arthritis 57 4 Background. Rheumatoid arthritis (RA) is a chronic inflammatory and destructive joint disease, characterized by overexpression of pro-inflammatory/-destructive genes and other activating genes (e.g., proto-oncogenes) in the synovial membrane (SM). The gene expression in disease is often characterized by significant inter-individual variances via specific synchronization/ desynchronization of gene expression. To elucidate the contribution of the variance to the pathogenesis of disease, expression variances were tested in SM samples of RA patients, osteoarthritis (OA) patients, and normal controls (NC).\r\nResults. For the comparison between RA and NC, 568 genes with significantly different variances in the 2 groups (p < 0.05; Bonferroni/Holm corrected Brown-Forsythe version of the Levene-Test) were selected. For the comparison between RA and OA, 333 genes were selected. Using the Kyoto encyclopedia of genes and genomes (KEGG), 10 pathways/complexes significantly affected by higher gene expression variances were identified in RA compared to NC, including cytokine – cytokine receptor interactions, the TGF-pathway, and anti-apoptosis.\r\nCompared to OA, 3 pathways with significantly higher variances were identified in RA (e.g., B cell receptor signaling, VEGF signaling). Functionally, the majority of the identified pathways is involved in the regulation of inflammation, proliferation, cell survival, and angiogenesis.\r\nConclusion. In RA, a number of disease-relevant or even disease-specific pathways/complexes are characterized by broad intra-group, inter-individual expression variances. This indicates that RA pathogenesis in different individuals may depend to a lesser extent on common alterations of the expression of specific key genes, but on individual-specific alterations of different genes resulting in common disturbances of key pathways.
GSE12051 ImmunoHuman Arthritis 44 1 We sought to find a gene-expression multigene predictor of response to infliximab therapy in Rheumatoid Arthritis patients. Using internal and external cross-validation systems we have built and validated an 8-gene predictor for response to infliximab.
GSE12109 ImmunoHuman Psoriasis 12 3 In this study, we shought to identify the cytokines produced by skin-resident T cells in normal skin, localize the receptors for these cytokines, and examine how these cytokines alter gene expression profiles of the cells bearing cognate receptors.
GSE12251 ImmunoHuman IBD 23 1 Infliximab, an anti-TNFa monoclonal antibody, is an effective treatment for ulcerative colitis (UC) inducing over 60% of patients to respond to treatment. Consequently, about 40% of patients do not respond. This study analyzed mucosal gene expression from patients enrolled in ACT1 to provide a predictive response signature for infliximab treatment.
GSE12384 ImmunoHuman Arthritis 24 2 A number of chronic, age-related diseases are associated with elevated markers of inflammation such as interleukin-6 (IL-6). In this study, we investigated the hypothesis that sedentary individuals with disparate basal serum IL-6 respond differentially to a structured physical activity programme. Gene expression changes in Peripheral Blood Mononuclear cells (PBMC) induced by physical activity was investigated in sedentary, middle-aged men (mean age 52.6 years and BMI 29.1), with relatively high or low basal serum IL-6 levels (mean of 2.13 and 0.59pg/ml respectively), who undertook a 24-week physical activity programme with blood sampling in the pre-exercise period and at the end of 24-weeks prescribed physical activity.
GSE12385 ImmunoHuman Arthritis 36 4 Gene expression changes in Peripheral Blood Mononuclear cells (PBMC) induced by physical activity was investigated in sedentary middle-aged men (mean age 52.6 years and BMI 29.1) who undertook a 24-week physical activity programme with blood sampling in the pre-exercise period , at the end of 24-weeks prescribed physical activity , and following a two-week detraining period.
GSE12472 ImmunoHuman COPD 63 7 Chronic obstructive pulmonary disease (COPD) and squamous cell lung carcinoma (SCC) are both smoking-related diseases. Interestingly, COPD itself is a risk factor for SCC, and this is independent of smoking history. Inferring from this knowledge, it is plausible to assume that patients with COPD may have a different gene expression profile in normal bronchial epithelium and in SCC. To test this hypothesis, we compared gene expression profiles in bronchial epithelium and in SCC from patients with and without COPD. Gene expression profiles were generated using whole human genome oligo microarrays for 28 laser microdissected histologically normal bronchial epithelium samples (10 without COPD, 18 with COPD) and 35 laser microdissected SCC samples (17 without COPD, 18 with COPD). We found no significant differences in gene expression levels between normal bronchial epithelium from patients with and without COPD. Remarkably, 374 genes were differentially expressed in SCC obtained from patients with or without COPD; 295 showed a higher expression level in SCC from patients with COPD and 79 genes showed higher expression levels in SCC from patients without COPD. Genes related to mitochondrial localization (n=44) and genes located on chromosomal arm 5q (n=34) were significantly overrepresented. For both categories, all genes showed a higher expression level in SCC from patients with COPD than from those without COPD. In conclusion, SCC from patients with COPD show a different gene expression profile compared to SCC from patients without COPD. This suggests that COPD related factors affect the gene expression signature in SCC.
GSE12685 ImmunoHuman AD 14 1 In Alzheimer’s disease (AD), early deficits in learning and memory are a consequence of synaptic modification which are likely induced by toxic beta-amyloid oligomers (oAß). To identify molecular targets downstream of oAß binding we prepared synaptoneurosomes from frontal cortex of control and IAD patients, and isolated mRNAs for comparison of gene expression. This approach elevated synaptic mRNAs above the threshold necessary for expression changes to be discriminated and also reduced other cellular mRNAs. In patients with minimal cognitive impairment (MCI) termed incipient AD (IAD) global measures of cognition declined with increasing levels of dimeric Aß (dAß). These patients also showed increased expression of neuroplasticity related genes, many encoding 3' UTR consensus sequences that regulate local translation in the synapse. One such gene, GluR2, displayed elevated mRNA and protein expression in IAD. Other neurotransmitter-related genes were also upregulated. Overexpressed genes may induce compensatory as well as negative effects on cognition and provide targets for intervention to moderate the response to dAß.
GSE12815 ImmunoHuman COPD 71 7 Cytologically normal airway epithelial samples were collected during bronchoscopy of current and former smokers. Subjects enrolled in this study were either under suspicion of having lung cancer, had dysplasia in their airway, or were a healthy current, former or never smoker. We supplemented existing GEO series (GSE4115 and GSE7895) with the samples in this study to explore PI3K pathway activity in the these cohorts.
GSE12860 ImmunoHuman Arthritis 20 9 Rheumatoid arthritis (RA) leads to progressive destruction of articular structures. Despite recent progress in controlling inflammation and pain, little cartilage repair has yet been observed. This in vitro study aims to determine the role of chondrocytes in RA-related cartilage destruction and antirheumatic drug-related regenerative processes. Human chondrocytes were three-dimensionally cultured in alginate beads. To determine the RA-induced gene expression pattern, human chondrocytes were stimulated with supernatant of RA synovial fibroblasts (RASF) and normal donor synovial fibroblasts (NDSF), respectively. To examine antirheumatic drug response signatures, human chondrocytes were stimulated with supernatant of RASF that have been treated with disease-modifying antirheumatic drugs (DMARD; azathioprine, sodium aurothiomalate, chloroquine phosphate, methotrexate), non-steroidal anti-inflammatory drugs (NSAID; piroxicam, diclofenac) or steroidal anti-inflammatory drugs (SAID; methylprednisolone, prednisolone). Genome-wide expression profiling with oligonucleotide microarrays was used to determine differentially expressed genes. Real-time RT-PCR and ELISA were performed for validation of microarray data. Following antirheumatic treatment, microarray analysis disclosed a reverted expression of 94 RA-induced chondrocyte genes involved in inflammation/NF-κB signalling, cytokine/chemokine activity, immune response, proliferation/differentiation and matrix remodelling. Hierarchical clustering analysis showed that treatment of RASF with the DMARD azathioprine, gold sodium thiomalate and methotrexate resulted in chondrocyte gene expression signatures that were closely related to the “healthy” pattern. Treatment with the SAID methylprednisolone and prednisolone strongly reverted the RA-related chondrocyte gene expression, in particular the expression of genes involved in inflammation/NF-κB and cytokine/chemokine activity. The NSAID piroxicam and diclofenac and the DMARD chloroquine phosphate had only moderate to marginal effects. Pathway analysis determined major mechanisms of drug action, for example pathways of cytokine-cytokine receptor interaction, TGF-β/TLR/Jak-STAT signalling and ECM-receptor interaction were targeted. This in vitro study provides a comprehensive molecular insight into the antirheumatic drug response signatures in human chondrocytes, thereby revealing potential molecular targets, pathways and mechanisms of drug action involved in chondrocyte regeneration. Thus, the present study may contribute to the development of novel therapeutic chondro-protective compounds and strategies.
GSE1297 ImmunoHuman AD 31 4 For these data, we analyzed hippocampal gene expression of nine control and 22 AD subjects of varying severity on 31 separate microarrays. We then tested the correlation of each gene's expression with MiniMental Status Examination (MMSE) and neurofibrillary tangle (NFT) scores across all 31 subjects regardless of diagnosis. These tests revealed a major transcriptional response comprising thousands of genes significantly correlated with AD markers. Several hundred of these genes were also correlated with AD markers across only control and incipient AD subjects (MMSE > 20).
GSE13168 ImmunoHuman Asthma 54 14 Glucocorticoids (GCs) and protein kinase A (PKA)-activating agents (beta-adrenergic receptor agonists) are mainstream asthma therapies based on their ability to prevent or reverse excessive airway smooth muscle (ASM) constriction. Their abilities to regulate another important feature of asthma - excessive ASM growth are poorly understood. Recent studies have suggested that GCs render agents of inflammation such as interleukin 1beta and tumor necrosis factor alpha mitogenic to ASM, via suppression of (antimitogenic) induced cyclooxygenase-2-dependent PKA activity. To further explore the mechanistic basis of these observations, we assessed the effects of epidermal growth factor and interleukin 1beta stimulation, and the modulatory effects of GC treatment and PKA inhibition, on the ASM transcriptome by microarray analysis.
GSE13355 ImmunoHuman Psoriasis 180 3 Gene expression has been proposed as an intermediate phenotype that can increase power in complex trait gene-mapping studies. Psoriasis, an immune-mediated, inflammatory and hyperproliferative disease of the skin and joints, provides an ideal model system to evaluate this paradigm, as conclusive evidence demonstrates that psoriasis has a genetic basis and the disease tissue is readily accessible.\r\nTo better understand the complex nature of processes in psoriasis, we characterize gene expression profiles in uninvolved and involved skin from affected individuals as well as normal skin from control individuals.
GSE13367 ImmunoHuman IBD 56 6 Background & Aims: Genome-wide gene expression (GWGE) profiles of mucosal colonic biopsies have suggested the existence of a continuous inflammatory state in quiescent ulcerative colitis (UC). The aim of this study was to use DNA microarray-based GWGE profiling of mucosal colonic biopsies and isolated colonocytes from UC patients and controls in order to identify the cell types responsible for the continuous inflammatory state. Methods: Adjacent mucosal colonic biopsies were obtained endoscopically from the descending colon in patients with active UC (n=8), quiescent UC (n=9), and with irritable bowel syndrome (controls, n=10). After isolation of colonocytes and subsequent extraction of total RNA, GWGE data were acquired using Human Genome U133 Plus 2.0 GeneChip Array (Affymetrix, Santa Clara, CA). Data analysis was carried out by principal component analysis and projection to latent structure-discriminant analysis using the SIMCA-P11 software (Umetrics, Umeå, Sweden). Results: A clear separation between active UC, quiescent UC and control biopsies were found, whereas the model for the colonocytes was unable to distinguish between quiescent UC and controls. The differentiation between quiescent UC and control biopsies was governed by unique profiles containing gene expressions with significant fold changes. These primarily belonged to the family of homeostatic chemokines revealing a plausible explanation to the abnormal regulated innate immune response seen in patients with UC. Conclusion: This study has demonstrated the presence of a continuous inflammatory state in quiescent UC, which seems to reflect an altered gene expression profile of lamina propria cells.
GSE13396 ImmunoHuman Asthma 34 4 Human Rhinovirus (HRV) infection can trigger exacerbations of asthma. Understanding of the mechanisms provoking airway inflammation and remodeling in asthma, as well as the pathogenic mechanisms of HRV infection and its association with asthma exacerbations, may offer significant opportunities for improved disease management. Genome-wide expression analysis of HRV type 1A-infected primary bronchial epithelial (PBE) cells from normal and asthmatic donors was performed to determine whether asthma is associated with a unique pattern of gene expression after HRV infection in vitro.
GSE13501 ImmunoHuman Arthritis 195 4 Objective: A multi-center study of recent onset juvenile idiopathic arthritis (JIA) subjects prior to treatment with DMARDS or biologics was undertaken to identify peripheral blood gene expression differences between JIA subclasses and controls. Methods: PBMC from 59 healthy children and 136 JIA subjects (28 enthesitis-related arthritis[ERA], 42 persistent oligoarthritis, 45 RF- polyarthritis, and 21 systemic) were isolated on Ficoll. Poly-A RNA was labeled using NuGEN Ovation and gene expression profiles were obtained using Affymetrix HG-U133 plus 2.0 Arrays. Results: 9,501 differentially expressed probe sets were identified among JIA subtypes and controls (ANOVA, FDR 5%). Specifically, 193, 1036, 873 and 7595 probe sets were different between controls and ERA, persistent oligoarthritis, RF- polyarthritis and systemic JIA samples respectively. In persistent oligoarthritis, RF- polyarthritis and systemic JIA subtypes, up-regulation of gene associated with IL-10 signaling was prominent. A hemoglobin cluster was identified that was under-expressed in ERA patients but over-expressed in systemic JIA. The influence of JAK/STAT, ERK/MAPK, IL-2 and B cell receptor signaling pathways was evident in persistent oligoarthritis. In systemic JIA, up regulation of innate immune pathways, including IL-6, TLR/IL1R, and PPAR signaling were noted, along with down regulation of gene networks related to NK and T cells. Complement and coagulation pathways were up-regulated in systemic JIA with a subset of these components differentially-expressed in the other three subtypes. Conclusions: Expression analysis identified differentially expressed genes in PBMCs between subclasses of JIA early in disease and controls, thus providing evidence for immunobiologic differences between these forms of childhood arthritis.
GSE13732 ImmunoHuman 2015Q2 113 2 Clinically isolated syndrome (CIS) refers to the earliest clinical manifestation of multiple sclerosis (MS). Currently there are no prognostic biological markers that accurately predict conversion of CIS to clinically definite MS (CDMS). Furthermore, the earliest molecular events in MS are still unknown. We used microarrays to study gene expression in naïve CD4+ T cells from 37 CIS patients at time of diagnosis and after one year. Supervised machine-learning methods were used to build predictive models of disease conversion. We identified 975 genes whose expression segregated CIS patients into 4 distinct subgroups. A subset of 108 genes further discriminated patients from one of these (group#1) from other CIS patients. Remarkably, 92% of patients from group #1 converted to CDMS within 9 months. Consistent downregulation of TOB1, a critical regulator of cell proliferation, was characteristic of group #1 patients. Decreased TOB1 expression at the RNA and protein levels was also confirmed in experimental autoimmune encephalomyelitis (EAE). Finally, a genetic association was observed between TOB1 variation and MS progression in an independent cohort. These results indicate that CIS patients at high risk of conversion have impaired regulation of T cell quiescence resulting in earlier activation of pathogenic CD4+ cells.
GSE13785 ImmunoHuman Asthma 22 4 Asthma is a heterogeneous disease. Exercise-induced bronchoconstriction (EIB) is a distinct syndrome that occurs in 30-50% of asthmatics and is characterized by high levels of pro-inflammatory eicosanoids. We identified genes differentially expressed in the airways of asthmatics with EIB relative to asthmatics without EIB. Genes related to epithelial repair and mast cell infiltration including beta-tryptase and carboxypeptidase A3 were upregulated by exercise challenge in the asthma group with EIB. We confirmed that two novel mediators trefoil factor 3 (TFF3) and transglutaminase 2 (TGM2) have increased expression in airways cells and secreted product in the airways. In vitro studies indicate that 1) TFF3 induces nitric oxide synthase in airway epithelial cells from asthmatics and 2) TGM2 augments the enzymatic activity of secreted phospholipase A2 (sPLA2) group X, an enzyme recently been implicated in asthma pathogenesis. Since PLA2 serves as the first rate-limiting step leading to eicosanoid generation, these results suggest that TGM2 may be a key initiator of the airway inflammatory cascade in asthma.
GSE13837 ImmunoHuman Arthritis 60 16 Background\r\nRheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by joint destruction and perpetuated by the synovial membrane (SM). In the inflamed SM, activated synovial fibroblasts (SFB) form the major cell type promoting development and progression of the disease by an abnormal expression/secretion of pro-inflammatory cytokines, tissue-degrading enzymes resulting in a predominant degradation of the extra-cellular matrix (ECM), and collagens causing joint fibrosis. We developed a new procedure, based on human knowledge and formal concept analysis (FCA), to simulate and analyze the temporal behaviour of regulatory and signaling networks. It was applied to a regulatory network (containing 18 genes from 5 functional groups) representing ECM formation and destruction in TGFβ - and TNFα -stimulated SFB.\r\nResults\r\nFor the modelling of SFB-controlled ECM turnover in rheumatic diseases, Boolean network architecture was used as well as extensive literature information and revision by experimental gene expression data from stimulated SFB. In course of revision, the additional experimental information resulted in different biologically reasonable changes, yielding two Boolean networks that describe TGFβ and TNFα effects, respectively. The final simulations were further analyzed by the attribute exploration algorithm of FCA, integrating again the observed time series in a more fine-grained and automated manner. The generated temporal rules clearly reveal subtle regulatory relationships between different genes, co-expression patterns and converse gene expression regulation in rheumatic diseases.\r\nConclusion\r\nThe developed Boolean network based method for the dynamical analysis of regulatory and signaling networks represents a reliable systems biological solution for the improved understanding of complex regulatory pathways and the interactions among different genes in disease. The resulting knowledge base can be used for further analysis of the ECM system in human fibroblasts and may be queried to predict the functional consequences of observed (e.g. in diseases as RA) or hypothetical (e.g. for therapeutic purposes) gene expression disturbances.
GSE13849 ImmunoHuman Arthritis 120 2 Objective. Microarray analysis was used to determine whether children with recent onset polyarticular juvenile idiopathic arthritis (JIA) exhibit biologically or clinically informative gene expression signatures in peripheral blood mononuclear cells (PBMC). Methods. Peripheral blood samples were obtained from 59 healthy children and 61 children with polyarticular JIA prior to treatment with second-line medications, such as methotrexate or biological agents. RNA was purified from Ficoll-isolated mononuclear cells, fluorescently labeled and then hybridized to Affymetrix U133 Plus 2.0 GeneChips. Data were analyzed using ANOVA at a 5% false discovery rate threshold after Robust Multi-Array Average pre-processing and Distance Weighted Discrimination normalization. Results. Initial analysis revealed 873 probe sets for genes that were differentially expressed between polyarticular JIA and controls. Hierarchical clustering of these probe sets distinguished three subgroups within polyarticular JIA. Prototypical subjects within each subgroup were identified and used to define subgroup-specific gene expression signatures. One of these signatures was associated with monocyte markers, another with transforming growth factor-beta-inducible genes, and a third with immediate-early genes. Correlation of these gene expression signatures with clinical and biological features of JIA subgroups suggests direct relevance to aspects of disease activity and supports the division of polyarticular JIA into distinct subsets. Conclusions. PBMC gene expression signatures in recent onset polyarticular JIA reflect discrete disease processes and offer a molecular classification of disease.
GSE13887 ImmunoHuman SLE 27 3 CD3-positive T cells were negatively isolated from 10 SLE patients and 9 healthy controls without SLE. All of the SLE samples and control samples were compared with one another to identify baseline differences in expression due to the disease. Next, T cell preparations from 4 of the control subjects were stimulated with either Nitric Oxide (NOC-18) 600 uM for 24hr or stimulated through CD3/CD28 for 24hr to determine which genes were responsive to these signaling mechanisms. Here, we show that activity of the mammalian target of rapamycin (mTOR), which is a sensor of the mitochondrial transmembrane potential, is increased in SLE T cells. Activation of mTOR was inducible by NO, a key trigger of MHP which in turn enhanced the expression of HRES-1/Rab4, a small GTPase that regulates recycling of surface receptors through early endosomes. Expression of HRES-1/Rab4 was increased in SLE T cells and, in accordance with its dominant impact on the endocytic recycling of CD4, it was inversely correlated with diminished CD4 expression. HRES-1/Rab4 over-expression was also inversely correlated with diminished TCR? protein levels. Combined with follow up studies, these results suggest that activation of mTOR causes the loss of TCR? in lupus T cells through HRES-1/Rab4-dependent lysosomal degradation.
GSE13896 ImmunoHuman COPD 70 2 Background: When exposed to specific stimuli, macrophages exhibit distinct activation programs, M1 and M2 polarization, that define macrophage function as inflammatory/immune effectors or anti-inflammatory/tissue remodeling cells, respectively. Due to their position on the lung epithelial surface, alveolar macrophages (AM) directly interact with environmental stimuli such as cigarette smoke, the major risk factor for the development of chronic obstructive pulmonary disease (COPD). Based on the current paradigm that, in response to smoking, AM contribute to both inflammatory and tissue remodeling processes in the lung relevant to the pathogenesis of COPD, we hypothesized that chronic exposure to cigarette smoking activates both the M1 and M2 polarization programs in AM. Methods and Findings: To assess this hypothesis, global transcriptional profiling with TaqMan confirmation and flow cytometry analysis was carried out on AM obtained by bronchoalveolar lavage of 24 healthy nonsmokers, 34 healthy smokers and 12 smokers with COPD to assess the expression of 41 M1 genes and 32 M2 genes in each group. Contrary to our expectations, while there was up-regulation of some genes typical for M2-related phenotypes, AM of healthy smokers exhibited substantial suppression of M1-related inflammatory/immune genes. These M1- and M2-related changes progressed with the development of smoking-induced lung disease, with AM of smokers with COPD exhibiting further down-regulation of M1-related genes accompanied with further up-regulation of some M2-related genes. Conclusion: The data demonstrates that the modifications of the AM transcriptome associated with smoking result in a unique phenotype characterized by reprogramming of AM towards M1-deactivated partially M2-polarized macrophages and suggests that, while AM likely contribute to smoking-induced tissue remodeling, the role of AM in the early pathogenesis of smoking-induced COPD in humans is not inflammatory. This concept is a departure from the conventional concept that AM-mediated inflammation participates in the early derangements of the lung induced by smoking, and suggests a novel paradigm for conceptualizing COPD and developing new approaches to prevent the development of smoking-induced lung disease.
GSE13917 ImmunoHuman Arthritis 10 2 B cell tolerance is established using deletion, anergy and receptor editing mediated by secondary recombination but it is unclear why autoreactive B cells choose a tolerance mechanism over another. We identified subgroups of patients with either rheumatoid arthritis or common variable immunodeficiency who presented defects in secondary recombination, which correlated with unusual CD21-/lo naïve B cells in their blood. CD21-/lo B cells were unable to induce calcium flux, get activated or proliferate in response to B cell receptor and/or CD40 triggering, suggesting that these B cells are anergic. Moreover, CD21-/lo B cells are often autoreactive and may express anti-nuclear antibodies. Thus, anergy can be a default tolerance mechanism mainly induced when receptor editing fails to silence developing autoreactive B cells.
GSE13931 ImmunoHuman COPD 98 2 Disparate Oxidant-related Gene Expression of Human Small Airway Epithelium Compared to Autologous Alveolar Macrophages in Response to the In Vivo Oxidant Stress of Cigarette Smoking\r\nThe oxidant burden of cigarette smoking induces lung cell dysfunction, and play a significant role in the pathogenesis of lung disease. Two cell populations directly exposed to the oxidants in cigarette smoke are the small airway epithelium and alveolar macrophages. Of these, the epithelium appears to be more vulnerable to smoking, becoming disordered in differentiation, repair and function, while alveolar macrophages become activated, without becoming diseased. In this context, we asked: for the same individuals, what is the baseline trancriptome of oxidant-related genes in small airway epithelium compared to alveolar macrophages and do the responses of the transcriptome of these 2 cell populations differ substantially to inhaled cigarette smoke? To address these questions we used microarray gene expression and TaqMan analysis to assess the gene expression profile of known oxidant-related genes in paired samples recovered by bronchoscopy from small airway epithelium and alveolar macrophages from the same healthy nonsmokers and normal smokers. Of the 155 oxidant-related genes surveyed, 122 (77%) were expressed in both cell populations in nonsmokers. However, of the genes expressed by both cell populations, oxidant related gene expression levels were higher in alveolar macrophages (67 genes, 43%) than small airway epithelium (37 genes, 24%). There were more oxidant-related genes uniquely expressed in the small airway epithelium (17%), than in alveolar macrophages (5%). In healthy smokers, the majority of oxidant-related genes were expressed in both cell populations, but there were marked differences in the numbers of oxidant-related genes that smoking up- or down-regulated. While smoking up-regulated 15 genes (10%) and down-regulated 7 genes (5%) in the small airway epithelium, smoking had far less effect on alveolar macrophages [only 4 (3%) genes up-regulated, and only 1 (0.6%) down-regulated]. Only a small number of smoking responsive oxidant-related genes overlapped between the two cell types (2 up-regulated, and no down-regulated genes). Consistent with this observation, pathway analysis of smoking-responsive genes in the small airway epithelium showed oxidant-related pathways dominated, but in alveolar macrophages immune-response pathways dominated. Thus, the responses of the oxidant-related transcriptome of cells with an identical genome and exposed to the same oxidant stress of cigarette smoking are very different, with responses of oxidant-related genes of alveolar macrophages far more subdued than that of small airway epithelium, consistent with the clinical observation that, while the small airway epithelium is vulnerable, alveolar macrophages are not "diseased" in response to the oxidant stress of cigarette smoking.
GSE13933 ImmunoHuman COPD 87 2 The initial site of smoking-induced lung disease is the small airway epithelium, which is difficult and time consuming to sample by fiberoptic bronchoscopy. We developed a rapid, office-based procedure to obtain trachea epithelium without conscious sedation from healthy nonsmokers (n=26) and healthy smokers (n=19, 27 ± 15 pack-yr). Gene expression differences [fold-change >1.5, p< 0.01, Benjamini-Hochberg correction] were assessed with Affymetrix microarrays. 1,057 probe sets were differentially expressed in healthy smokers vs nonsmokers, representing >500 genes. Trachea gene expression was compared to an independent group of small airway epithelial samples (n=23 healthy nonsmokers, n=19 healthy smokers, 25 ± 12 pack-yr). The trachea epithelium is more sensitive to smoking, responding with 3-fold more differentially-expressed genes than small airway epithelium. The trachea transcriptome paralleled the small airway epithelium, with 156 of 167 (93%) genes that are significantly up- and down-regulated by smoking in the small airway epithelium showing similar direction and magnitude of response to smoking in the trachea. Trachea epithelium can be obtained without conscious sedation, representing a less invasive surrogate “canary” for smoking-induced changes in the small airway epithelium. This should prove useful in epidemiologic studies correlating gene expression with clinical outcome in assessing smoking-induced lung disease.
GSE14000 ImmunoHuman Inflammation 24 4 Dendritic cells (DCs) are the sentinels of the mammalian immune system and they undergo a complex maturation process mediated by activation upon pathogen detection. Recent studies described the analysis of activated DCs by transcriptional profiling, but translation regulation was never taken in account. Therefore, the nature of the mRNAs being translated at various stages of DC activation was determined with the help of translational profiling, which is the sucrose gradient fractionation of polysomal-bound mRNAs combined to microarrays analysis. Total and polysomal-bound mRNA populations were compared in immature (0h) and LPS-stimulated (4h and 16h) human monocyte-derived DCs with the help of Affymetrix microarrays. Biostatistical analysis indicated that 296 mRNA molecules are translationally regulated during DC-activation. The most abundant biological process among the regulated mRNAs was protein biosynthesis, indicating the existence of a negative feedback loop regulating translation. Interestingly, a cluster of 17 ribosomal proteins were part of the regulated mRNAs, indicating that translation may be fine-tuned by particular components of the translational machinery. Our observations highlight the importance of translation regulation during the immune response, and may favour the identification of novel gene clusters or protein networks relevant for immunity. Our study also provides information on the possible absence of correlation between gene expression and real protein production in DCs.
GSE1402 ImmunoHuman Arthritis 57 2 Biotinylated cRNA was synthesized from total RNA (Enzo; Farmingdale, NY) and processed according to the Affymetrix GeneChip Expression Analysis Technical Manual (Affymetrix; Santa Clara, CA). 57 samples: 5 pauciarticular PBMC, 15 polyarticular PBMC, 11 control PMBC, 6 JSpA PBMC, 5 pauciarticular SFMC, 10 polyarticular PBMC, 5 JSpA SFMC classified by course.
GSE14386 ImmunoHuman 2015Q2 30 1 IFNß, an effective therapy against relapsing-remitting (RR) multiple sclerosis (MS) is naturally secreted during the innate immune response against viral pathogens. The objective of this study was to characterize the immunomodulatory mechanisms of IFNß targeting innate immune response and their effects on DC-mediated regulation of T-cell differentiation. We found that IFNß-1a in-vitro treatment of human monocyte-derived dendritic cells (DCs) induced the expression of TLR7 and the members of its downstream signaling pathway, including myeloid differentiation factor 88 (MyD88), IL-1R-associated kinase (IRAK)4, and TNF receptor-associated factor (TRAF)6, while it inhibited the expression of IL-1R. Using siRNA TLR7 gene silencing, we confirmed that IFNß-1a-induced changes in MyD88, IRAK4 and IL-1R expression were dependent on TLR7. TLR7 expression was also necessary for the IFNß-1a-induced inhibition of IL-1ß and IL-23, and the induction of IL-27 secretion by DCs. Supernatant (SN) transfer experiments confirmed that IFNß-1a-induced changes in DCs’ cytokine secretion inhibit Th17 cell differentiation as evidenced by the inhibition of retinoic acid-related orphan nuclear hormone receptor C (RORC) and IL-17A gene expression and IL-17A secretion. Our study has identified a novel therapeutic mechanism of IFNß-1a, that selectively targets the autoimmune response in MS.
GSE14580 ImmunoHuman IBD 30 2 Infliximab, an anti-TNF-alpha monoclonal antibody, is an effective treatment for ulcerative colitis (UC) with over 60% of patients responding to treatment and up to 30% reaching remission. The mechanism of resistance to anti-TNF-alpha is unknown. This study used colonic mucosal gene expression to provide a predictive response signature for infliximab treatment in UC.
GSE14905 ImmunoHuman Psoriasis 82 3 We observed robust overexpression of type I interferon (IFN)–inducible genes and genomic signatures that indicate T cell and dendritic cell infiltration in lesional skin. Up-regulation of mRNAs for IFN-a subtypes was observed in lesional skin compared with nonlesional skin. Enrichment of mature dendritic cells and 2 type I IFN–inducible proteins, STAT1 and ISG15, were observed in the majority of lesional skin biopsies. Concordant overexpression of IFN-c and TNF-a–inducible gene signatures occurred at the same disease sites.
GSE15083 ImmunoHuman Arthritis 21 1 Children with oligoarticular JIA (arthritis in 4 or fewer joints) can either continue to have this mild form of arthritis (persistent oligoarticular JIA) or extend to a more sever form involving more than 4 joints (extended oligoarticular JIA)\r\nSynovial fluid mononuclear cell RNA was prepared from 21 recently diagnosed pre-treatment patients and grouped according to whether the patient had extended or persisted at one year after diagnosis
GSE15197 ImmunoHuman PulmonaryFibrosis 39 2 Idiopathic pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by pulmonary arteriolar remodeling, and is frequently associated with right heart failure. This study identifies significant novel biological changes in eight genes and several genetic pathways, that were likely to contribute to the pathogenesis of PAH. We also demonstrate that PAH and PH secondary to idiopathic pulmonary fibrosis (IPF) are characterized by distinct gene expression signatures, implying distinct pathophysiological mechanisms.
GSE15222 ImmunoHuman AD 363 0 We recently surveyed the relationship between the human brain transcriptome and genome in a series of neuropathologically normal postmortem samples. We now have analyzed additional samples with a confirmed pathologic diagnosis of late onset Alzheimer's disease (LOAD, final n=187 controls, 176 cases). Nine percent of the cortical transcripts we analyzed had expression profiles correlated with their genotypes in the combined cohort and approximately 5% of transcripts had SNP-transcript relationships that could distinguish LOAD samples. Two of these transcripts have been previously implicated in LOAD candidate gene SNP-expression screens. This study shows how the relationship between common inherited genetic variants and brain transcript expression can be used in the study of human brain disorders. We suggest that studying the transcriptome as a quantitative endo-phenotype has greater power to find risk SNPs influencing expression than the use of discrete diagnostic categories such as presence or absence of disease. see DOI:10.1016/j.ajhg.2009.03.011 for further details and complete author list.
GSE15227 ImmunoHuman Arthritis 15 1 Asporin, also known as periodontal ligament-associated protein 1 (PLAP1), is a member of the family of small leucine-rich proteoglycan (SLRP) family. It is present within the cartilage extracellular matrix (ECM), and is reported have a genetic association with osteoarthritis. Its D14 allele has recently been found to be associated with lumbar disc degeneration in Asian subjects. There have been no studies, however, of this gene’s normal immunohistochemical localization within the human intervertebral disc, nor of expression levels in Caucasian individuals with disc degeneration. Studies were approved by our human subjects Institutional Review Board. Methods included immunohistochemical localization of asporin in the disc of humans and the sand rat (a small rodent with spontaneous age-related disc degeneration), and Affymetrix microarray analysis of asporin gene expression in vivo and in vitro.\r\nmmunohistochemical studies of human discs revealed that some, but not all, cells of the outer annulus expressed asporin. Fewer cells in the inner annulus contained asporin, and it was rarely present in cells in the nucleus pulposus. Similar patterns were found for the presence of asporin in lumbar discs of sand rats. Substantial relative gene expression levels were seen for asporin in both disc tissue and in annulus cells grown in three-dimensional culture. More degenerate human discs (Thompson grade 4) showed higher expression levels of asporin than did less degenerate (grade 1, 2 and 3) discs, p = 0.004. In the discs of Caucasian subjects studied here, and in the sand rat, greater immunolocalization levels were found in the outer compared to inner annulus. Localization was rare in the nucleus. Gene expression studies showed greatest expression of asporin in the more degenerate human discs in vivo.
GSE15245 ImmunoHuman 2015Q2 94 2 Background: The ability to predict the spatial frequency of relapses in multiple sclerosis (MS) would enable treating physicians to decide when to intervene more aggressively and to plan clinical trials more accurately. Methods: In the current study our objective was to determine if subsets of genes can predict the time to the next acute relapse in patients with MS. Data-mining and predictive modeling tools were utilized to analyze a gene-expression dataset of 94 non-treated patients; 62 patients with definite MS and 32 patients with clinically isolated syndrome (CIS). The dataset included the expression levels of 10,594 genes and annotated sequences corresponding to 22,215 gene-transcripts that appear in the microarray. Results: We designed a two stage predictor. The first stage predictor was based on the expression level of 10 genes, and predicted the time to next relapse with a resolution of 500 days (error rate 0.079, p< 0.001). If the predicted relapse was to occur in less than 500 days, a second stage predictor based on an additional different set of 9 genes was used, resulting in a prediction with a resolution of 50 days as to the timing of the next relapse. The error rate of this predictor was 2.3 fold lower than the error rate of random predictions (error rate = 0.35, p<0.001). The predictors were further evaluated and found effective not only in untreated patients but were also valid for MS patients which subsequently received immunomodulatory treatments after the initial testing (the error rate of the first level predictor was < 0.18 with p<0.001 for all the patient groups). Conclusions: We conclude that gene expression analysis is a valuable tool that can be used in clinical practice to predict future MS disease activity. Similar approach can be also useful for dealing with other autoimmune diseases that characterized by relapsing-remitting nature
GSE15258 ImmunoHuman Arthritis 86 1 The whole blood was collected pre-treatment from rheumatoid arthritis patients starting the anti_TNF therapy. All patients were naïve to anti_TNFs. The disease activity was measured using the DAS28 score at the pre-treatment visit1 (DAS28_v1) and 14 weeks after treatment visit3 (DAS28_v3). The response to the therapy was evaluated using the EULAR [European League Against Rheumatism] definition of the response. The objective of the data analysis was to identify gene expression coorelating with response as well as to identify genes that differentiate responders versus non-responders pre-treatment. The results of this investigation identified 8 trainscripts that predict responders vs. non-responders with 89% accuracy.
GSE15316 ImmunoHuman Arthritis 23 3 New and effective therapeutical options are available for the treatment of Rheumatoid Arthritis. One of such treatments is rituximab, and chimeric anti-CD20 antibody that selectively depletes the CD20+ B cell subpopulation.\r\nSimilar to established anti-TNF alpha therapies, there is a subgroup of RA patients that do not experience significant clinical response. Therefore, one of the major necessities in actual RA therapeutical management is to identify reliable predictors of the response to this therapies. In the present study we have evaluated 3 blood cell types (i.e. whole blood, isolated B cells and isolated CD4 T cells) using microarray gene expression profiling to identify their potential use as biomarkers for rituximab response.\r\nIn all three tissues evaluated, we have identified statistically significant differentially expressed genes. The most relevant candidates have been reevaluated using RealTime PCR. These genes were: TRAF1 and arginase 1 in whole blood, Toll-Like Receptor 4 (TLR4) in CD4+ T cells and AT-rich interactive domain 3A (ARID3A) in B cells.\r\nIn the present study we have demonstrated the potential of different blood cell types for the prediction of the response to rituximab. In particular, we have found a set of relevant candidate genes that could be the basis for future treatment response prediction.
GSE15573 ImmunoHuman Arthritis 33 1 Large-scale gene expression profiling of peripheral blood mononuclear cells from Rheumatoid Arthritis (RA) patients could provide a molecular description that reflects the contribution of diverse cellular responses associated with this disease. The aim of our study is to identify peripheral blood gene expression profiles for RA patients, using Illumina technology, to gain insights into RA molecular mechanisms. The Illumina Human-6v2 Expression BeadChips were used for a complete genome-wide transcript profiling of peripheral blood mononuclear cells from 18 RA patients and 15 Controls. Differential analysis per gene was performed with one-way analysis of variance (ANOVA) and P values were adjusted to control the False Discovery Rate (FDR<5%). Genes differentially expressed at significant level between patients and controls were analyzed using Gene Ontology (GO) in the PANTHER database to identify biological processes. A differentially expression of 339 Reference Sequence genes (238 down-regulated and 101 up-regulated) between the two groups was observed. We identified a remarkably elevated expression of a spectrum of genes involved in Immunity and Defense in peripheral blood mononuclear cells of RA patients compared to Controls. This result is confirmed by GO analysis, suggesting that these genes could be activated systemically in RA. No significant down-regulated ontology groups were found. Microarrays data were validated by real time PCR in a set of nine genes showing a high degree of correlation. Our study highlighted several new genes that could contribute in the identification of innovative clinical biomarkers for diagnostic procedures and therapeutic intervention. Further studies on larger scale groups of patients should be performed with the same technology to replicate these results and to allow clinical stratification.
GSE15602 ImmunoHuman Arthritis 11 2 TNF antagonists are routinely used in severe rheumatoid arthritis (RA) patients who failed conventional DMARD therapy. According to large clinical trials, the three available drugs (adalimumab, infliximab and etanercept) display similar effects in terms of efficacy, tolerability and side effects. These studies also indicate that about 25% of RA patients treated with TNF-antagonists do not display any significant clinical improvement.\r\nThe aim of this study was to investigate global molecular patterns in synovial biopsies from RA patients obtained 12 weeks after initiation of adalimumab therapy.
GSE15615 ImmunoHuman Arthritis 6 1 TNFalpha and IL1beta play a pathogenic role in rheumatoid arthritis. Both cytokines are known to activate cytokine and metalloproteinase secretion by synovial fibroblasts. In the present study, we wanted to investigate whether TNFalpha and IL1beta displayed differential effects on cultured Fibroblast-like Synovial Cells derived from RA patients. Global gene expression analyses indicated that both cytokines induced similar genes in these cells.
GSE15645 ImmunoHuman Arthritis 42 3 Identify biomarkers to predict response to therapy in polyarticular juvenile idiopathic arthritis (JIA) using gene expression microarrays.
GSE15823 ImmunoHuman Asthma 12 2 Asthma pathogenesis and susceptibility involves a complex interplay between genetic and environmental factors.\r\nWe report the results of expression microarray studies using tissue obtained from bronchial biopsies of healthy controls and of subjects with allergic asthma, both before and following inhaled corticotherapy.
GSE16031 ImmunoHuman SystemicSclerosis 48 3 The development of a comparison approach for Illumina bead chips unravels unexpected challenges applying newest generation microarrays\r\nThe MAQC project demonstrated that microarrays with comparable content show inter- and intra-platform reproducibility. However, since the content of gene databases still increases, the development of new generations of microarrays covering new content is mandatory. To better understand the potential challenges updated microarray content might pose on clinical and biological projects we developed a methodology consisting of in silico analyses combined with performance analysis using real biological samples. Here we clearly demonstrate that not only oligonucleotide design but also database content and annotation strongly influence comparability and performance of subsequent generations of microarrays. Additionally, using human blood samples and purified T lymphocyte subsets as two independent examples, we show that a performance analysis using biological samples is crucial for the assessment of consistency and differences. This study provides an important resource assisting investigators in comparing microarrays of updated content especially when working in a clinical or regulatory setting.
GSE16032 ImmunoHuman Asthma 10 1 Severe asthma exacerbations in children requiring hospitalisation are typically associated with viral infection, and occur almost exclusively amongst atopics, but the significance of these comorbidities is unknown. We hypothesised that underlying interactions between immunoinflammatory pathways related to responses to aeroallergen and virus are involved, and that evidence of these interactions is detectable in circulating cells during exacerbations.\r\nTo address this hypothesis we used a genomics-based approach involving profiling of PBMC subpopulations collected during acute exacerbation versus convalescence by microarray and flow cytometry.
GSE16054 ImmunoHuman LungDisease 9 2 Mutations in the SFTPC gene associated with interstitial lung disease in human patients result in misfolding, endoplasmic reticulum (ER) retention, and degradation of the encoded surfactant protein C (SP-C) proprotein. To identify candidate genes involved in ER quality control of SP-C, HEK293 cells were transiently transfected with mutant SP-C (SP-C?exon4 or SP-CL188Q), SP-CWT, or vector cDNAs, and global changes in gene expression were assessed by microarray analyses. Microarray analysis demonstrated that the SPC exon 4 deletion and SPC L188Q mutations invoke very similar transcriptional profiles including the activation of major players mediating ER response and unfolding protein response (UPR) in transient transfection system. In combination with promoter scan (UPRE, ERSE, XBP1 sites) and protein domain analysis (Finding ER Lumen, ER Membrane retention signal, J-Domain and Leucine Zipper domain), we were able to not only verify the known ERAD components (XBP1, Bip, Erdj4&5), but also identify multiple ER components which may play critical roles in the detection and /or degradation of mutant SPC, which in turn will help us to gain better understanding of the entire mammalian ERAD machinery.
GSE16161 ImmunoHuman 2015Q2 33 1 In this study we used genomic profiling to characterize differences in expression of genes related to epidermal growth/differentiation and inflammatory circuits in skin lesions of psoriasis and atopic dermatitis (AD), comparing expression values to normal skin. Skin biopsies were collected from 9 patients with chronic atopic dermatitis, 15 psoriasis patients, and 9 healthy volunteers.
GSE16193 ImmunoHuman COPD 20 3 Carbon monoxide (CO) is an endogenous messenger that suppresses inflammation, modulates apoptosis and promotes vascular remodeling. Here, microarrays were employed to globally characterize the CO (250 ppm) suppression of early (1 h) LPS-induced inflammation in human monocytic THP-1 cells. CO suppressed 79 of 101 immediate-early genes induced by LPS; 19% (15/79) were transcription factors and most others were cytokines, chemokines and immune response genes. The prototypic effects of CO on transcription and protein production occurred early but decreased rapidly. CO activated p38 MAPK, ERK1/2 and Akt and caused an early and transitory delay in LPS-induced JNK activation. However, selective inhibitors of these kinases failed to block CO suppression of LPS-induced IL-1beta, an inflammation marker. Of CO-suppressed genes, 81% (64/79) were found to have promoters with putative NF-kappaB binding sites. CO was subsequently shown to block LPS-induced phosphorylation and degradation of IkappaBalpha in human monocytes, thereby inhibiting NF-kappaB signal transduction. CO broadly suppresses the initial inflammatory response of human monocytes to LPS by reshaping proximal events in TLR4 signal transduction such as stress kinase responses and early NF-kappaB activation. These rapid, but transient effects of CO may have therapeutic applications in acute pulmonary and vascular injury.
GSE16395 ImmunoHuman LungDisease 48 2 Langerhans-cell histiocytosis (LCH) is characterized by heterogeneous lesions containing CD207+ Langerhans cells (LCs) and lymphocytes. In this study, we isolated CD207+ cells and CD3+ T cells from LCH lesions to determine cell-specific gene expression. Compared to control epidermal CD207+ cells, the LCH CD207+ cells yielded 2113 differentially-expressed genes (FDR<0.01). Surprisingly, expression of many genes previously associated with LCH, including cell-cycle regulators, pro-inflammatory cytokines and chemokines were not significantly different from control LCs in our study. However, several novel genes whose products activate and recruit T cells to sites of inflammation, including SPP1 (osteopontin), were highly over-expressed in LCH CD207+ cells. Furthermore, several genes associated with immature myeloid dendritic cells were over-expressed in LCH CD207+ cells. Compared to the peripheral CD3+ cells from LCH patients, the LCH lesion CD3+ cells yielded only 162 differentially-regulated genes (FDR<0.01), and the expression profile of the LCH lesion CD3+ cells was consistent with an activated regulatory T cell phenotype with increased expression of FOXP3, CTLA4 as well as SPP1. Based on these results, we propose a new model of LCH pathogenesis in which lesions do not arise from epidermal Langerhans cells, but from accumulation of bone-marrow derived immature myeloid dendritic cells that recruit activated lymphocytes.
GSE16464 ImmunoHuman Arthritis 12 2 Autologous chondrocyte transplantation (ACT) is a routine technique to regenerate focal cartilage lesions. However, patients with osteoarthritis (OA) are lacking an appropriate long-lasting treatment alternative, partly since it is not known if chondrocytes from OA patients have the same chondrogenic differentiation potential as chondrocytes from donors not affected by OA. Articular chondrocytes from patients with OA undergoing total knee replacement (Mankin Score >3, Ahlbäck Score >2) and from patients undergoing ACT, here referred to as normal donors (ND), were isolated applying protocols used for ACT. Their chondrogenic differentiation potential was evaluated both in high-density pellet and scaffold (Hyaff-11) cultures by histological proteoglycan assessment (Bern Score) and immunohistochemistry for collagen types I and II. Chondrocytes cultured in monolayer and scaffolds were subjected to gene expression profiling using genome-wide oligonucleotide microarrays. Expression data were verified by using quantitative RT-PCR. Chondrocytes from ND and OA donors demonstrated accumulation of comparable amounts of cartilage matrix components, including sulphated proteoglycans and collagen types I and II. The mRNA expression of cartilage markers (COL2A1, COMP, aggrecan, CRTL1, SOX9) and genes involved in matrix synthesis (biglycan, COL9A2, COL11A1, TIMP4, CILP2) was highly induced in 3D cultures of chondrocytes from both donor groups. Genes associated with hypertrophic or OA cartilage (COL10A1, RUNX2, periostin, ALP, PTHR1, MMP13, COL1A1, COL3A1) were not significantly regulated between the two groups of donors. The expression of 661 genes, including COMP, FN1, and SOX9, were differentially regulated between OA and ND chondrocytes cultured in monolayer. During scaffold culture, the differences diminished between the OA and ND chondrocytes, and only 184 genes were differentially regulated. Only few genes were differentially expressed between OA and ND chondrocytes in Hyaff-11 culture. The risk of differentiation into hypertrophic cartilage does not seem to be increased for OA chondrocytes. Our findings suggest that the chondrogenic capacity is not significantly affected by OA and OA chondrocytes fulfill the requirements for matrix-associated ACT.
GSE1650 ImmunoHuman COPD 30 1 Comparison of severely emphysematous tissue removed at lung volume reduction surgery to that of normal or mildly emphysematous lung tissue resected from smokers with nodules suspicious for lung cancer.\r\nData obtained from the 18 patients with severe emphysema and 12 patients with mild/no emphysema.\r\nResearch may provide insights into the pathogenetic mechanisms involved in chronic obstructive pulmonary disease (COPD).
GSE16538 ImmunoHuman LungDisease 12 1 We hypothesized that tissue genome-wide gene expression analysis, coupled with gene network analyses of differentially expressed genes, would provide novel insights into the pathogenesis of pulmonary sarcoidosis.
GSE16696 ImmunoHuman COPD 50 1 Background: Whereas cilia damage and reduced cilia beat frequency have been implicated as causative of reduced mucociliary clearance in smokers, theoretically mucociliary clearance could also be affected by cilia length. Based on models of mucociliary clearance predicting cilia length must exceed the 6 -7 µm airway surface fluid depth to generate force in the mucus layer, we hypothesized cilia height may be decreased in airway epithelium of normal smokers compared to nonsmokers.\r\nMethodology/Principal Findings: Cilia length in normal nonsmokers and smokers was evaluated in aldehyde-fixed, paraffin-embedded endobronchial biopsies, and air-dried and hydrated samples brushed from human airway epithelium via fiberoptic bronchoscopy. In 28 endobronchial biopsies, healthy smoker cilia length was reduced 15% compared to nonsmokers (p<0.05). In 47 air-dried samples of airway epithelial cells, smoker cilia length was reduced 13% compared to nonsmokers (p<0.0001). Analysis of the length of individual, detached cilia in 17 samples, smoker cilia length was reduced 9% compared to nonsmokers (p<0.05). Finally, in 16 fully hydrated, unfixed samples, smoker cilia length was reduced 7% compared to nonsmokers (p<0.05).
GSE16759 ImmunoHuman AD 8 1 In this study, we jointly profiled mRNA and miRNA expression to determine the role of miRNAs in AD, and whether the levels of miRNAs are related to those of target mRNAs. We found a bias towards positive correlation between levels of miRNAs and those of their targets.
GSE16879 ImmunoHuman IBD 133 12 We used microarrays to identify mucosal gene signatures predictive of response to infliximab (IFX) in patients with inflammatory bowel disease (IBD) and to gain more insight into the pathogenesis of IBD.
GSE16972 ImmunoHuman COPD 12 1 Rationale: Chronic Obstructive Pulmonary Disease (COPD) is considered a chronic inflammatory disease characterized by progressive airflow limitation and also has significant extrapulmonary (systemic) effects that lead to comorbid conditions. Very little is known about the pathomechanism of the disease.\r\nObjectives: Among inflammatory cell types, alveolar macrophages appear to have a key role in initiating and/or sustaining disease progression. These cells are derived from peripheral monocytes. Identification of disease and cell type specific gene expression profiles can be revealing and also practically useful in order to diagnose and characterize disease progression and the effect of drug treatment.\r\nMethods: We used Affymetrix microarrays to obtain gene expression data of alveolar macrophages and circulating monocytes of COPD and healthy control patients. The microarray results were confirmed by quantitative real-time polymerase chain reaction in multiple patient collections.\r\nMeasurements and Main Results: We have identified gene sets specifically associated with COPD in alveolar macrophages and also in monocytes. Immune function, responses to stimuli, and cell death related genes appear to be impacted in both cell types. Remarkably, there is an overlapping gene set between the two cell types.\r\nConclusions: Taken together, our data show that COPD-specific gene signatures can be identified and validated, and that the disease also affects peripheral monocytes. Moreover, monocytes and alveolar macrophages carry overlapping gene expression signatures. Our findings further support the notion that altered responsiveness to stimuli is the key characteristic of alveolar macrophages and also of their precursors, peripheral monocytes.
GSE17048 ImmunoHuman 2015Q2 144 3 We measured mRNA expression for all known genes in whole blood from 144 individuals, 99 with MS (43 PPMS, 36 RRMS and 20 SPMS). Analysis of gene expression and genotype in these individuals has indicated the dominant genetic association with T cell regulation is matched by the dominant pattern of dysregulation of T cell gene expression in MS and its clinical subtypes.
GSE17204 ImmunoHuman PD 8 1 DJ-1 is an atypical peroxiredoxin-like peroxidase that may act as a redox-dependent chaperone and a regulator of transcription. To explore DJ-1-mediated transcriptional control in Parkinson’s disease (PD), we generated human neuroblastoma cells with inducible knock-down of DJ-1 expression. We then used functional genomic techniques to identify novel pathways dysregulated by loss of DJ-1 function. Using microarray gene expression profiling, we found that DJ-1 silencing alters the expression of 26 genes, with 10 down-regulated and 16 up-regulated transcripts. Among the down-regulated genes we found Ret, tyrosine kinase receptor for the neurotrophic factor GDNF. Taking advantage of Ingenuity Pathways Analysis, we identified hypoxia inducible factor 1 alpha (Hif1a) as a possible mediator of the interplay between DJ-1 and Ret. We show that Hif1a is stabilized in the absence of DJ-1, and that loss of DJ-1 generates hypoxia and accumulation of free radical species (ROS). Overexpression of wt DJ-1, but not of C106A and L166P mutants deficient in ROS scavenger activity, rescues Ret expression in neuroblastoma cells. These findings reveal novel players in PD pathogenesis and provide evidence for additional pathways involved in DJ-1-mediated neurodegeneration.
GSE17393 ImmunoHuman 2015Q2 15 1 Background: pregnancy is associated with reduced activity of multiple sclerosis (MS). However, the biological mechanisms underlying this pregnancy-related decrease in disease activity are poorly understood.\r\nThis data series contains the subset of data used to generate a MS signature comparing female healthy specimens with respect to MS patients
GSE17449 ImmunoHuman 2015Q2 28 2 This SuperSeries is composed of the SubSeries listed below.
GSE17590 ImmunoHuman Arthritis 85 1 Background: Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) is a rare disease associated with dysregulated interleukin (IL)-1 activity. Objectives: To assess the efficacy and safety of Anakinra, an IL-1 receptor antagonist in SJIA and its effects on gene expression profiling. Methods: We conducted a multicenter, randomized, double-blind placebo-controlled trial. The primary objective was to compare the efficacy of a one-month treatment with anakinra (2 mg/kg subcutaneoulsy daily, maximum 100 mg) to a placebo between 2 groups of 12 SJIA patients each. Response was defined by a 30% improvement of the pediatric American College of Rheumatology criteria for JIA, resolution of systemic symptoms and a decrease of at least 50% of both C-reactive protein and erythrocyte sedimentation rate compared to baseline. An intention-to-treat analyze was performed. After Month 1 (M1), patients taking placebo were switched to Anakinra. Secondary objectives included tolerance and efficacy assessment for 12 months. Results: At M1, concluding the randomized trial, there was a significant difference in the response rate between patients treated with Anakinra (8/12 responders) and placebo (1/12) (p=0.003). The number of adverse events, mainly pain to injections, was similar between both groups. Ten patients from the placebo group switched to Anakinra at M1; nine were responders at M2. Between M1 and M12, six patients stopped treatment for an adverse event (Crohn’s disease, hepatitis), a lack of efficacy or a disease flare (2 cases each). Blood gene expression profiling at enrollment and upon follow-up allowed us to identify one set of dysregulated genes that reverted to normal values in the clinical responders and a second set, including interferon-inducible genes, that was induced by Anakinra. Conclusion: Anakinra is an effective treatment of SJIA. Its effect is associated with normalization of blood gene expression profiles in clinical responders and de novo induction of an interferon signature. (Clinical trials registration number: NCT00339157)
GSE1786 ImmunoHuman COPD 24 2 Needle biopsies were obtained from the vastus lateralis muscle of 6 healthy, sedentary, 67±2.5 year-old males before and after 3 months of training.
GSE18309 ImmunoHuman AD 9 2 With the aging population, there is a growing focus on dementia, especially Alzheimer’s disease (AD). The molecular basis underlying the pathogenesis of AD is gradually being elucidated. Increasing evidence has shown that the immunological function of leukocytes plays a crucial role in the development of neurodegenerative disorders. However, there have been few studies among the Taiwanese population.\r\nThe aim of this study was to investigate potential biomarkers for early diagnosis of Alzheimer’s disease from blood leukocytes.
GSE18632 ImmunoHuman ALS 8 1 TDP-43 is an RNA/DNA-binding protein implicated in transcriptional repression and mRNA processing. Inclusions of TDP-43 are hallmarks of frontotemporal dementias and amyotrophic lateral sclerosis. Besides aggregation of TDP-43, loss of nuclear localization is observed in disease. To identify relevant targets of TDP-43, we performed an expression profiling study. Thereby, histone deacetylase 6 (HDAC6) downregulation was discovered upon TDP-43 silencing on mRNA and protein level in human embryonic kidney HEK293E and neuronal SH-SY5Y cells. This was accompanied by accumulation of the major HDAC6 substrate, acetyl-tubulin. Expression of wild-type but neither RNA-binding- nor nuclear-localization-deficient TDP-43 restored HDAC6 expression. Moreover, TDP-43 bound specifically to HDAC6 mRNA arguing for a direct functional interaction. Importantly, in vivo validation in TDP-43 knockout Drosophila melanogaster also showed HDAC6 mRNA decrease. HDAC6 is necessary for protein aggregate formation and degradation. Indeed, downregulation of HDAC6 reduced aggregate formation and increased cytotoxicity of expanded poly-glutamine ataxin-3 in TDP-43 silenced cells. This was completely restored by co-transfection with HDAC6. In conclusion, loss of functional TDP-43 causes HDAC6 downregulation and might thereby contribute to pathogenesis.
GSE18637 ImmunoHuman nomodel 20 0 Human airway epithelial cells cultured in vitro at air-liquid interface (ALI) form a pseudostratified epithelium that forms tight junctions and cilia, and produces mucin, and are widely used as a model of differentiation, injury, and repair. To assess how closely the transcriptome of ALI epithelium matches that of in vivo airway epithelial cells, we used microarrays to compare the transcriptome of human large airway epithelial cells cultured at ALI with the transcriptome of large airway epithelium obtained via bronchoscopy and brushing. Gene expression profiling showed global gene expression correlated well between ALI cells and brushed cells, but there were some differences. Gene expression patterns mirrored differences in proportions of cell types (ALI have higher percentages of basal cells, brushed cells have higher percentages of ciliated cells), with ALI cells expressing higher levels of basal cell-related genes and brushed cells expressing higher levels of cilia-related genes. Pathway analysis showed ALI cells had increased expression of cell cycle and proliferation genes, while brushed cells had increased expression of cytoskeletal organization and humoral immune response genes. Overall, ALI cells are a good representation of the in vivo airway epithelial transcriptome, but for some biologic questions, the differences in the in vitro vs in vivo environments need to be considered.
GSE18651 ImmunoHuman PulmonaryFibrosis 9 2 TGFß is one of most intensively studied regulators of extracellular matrix formation, and has been implicated in the development of pulmonary fibrosis in different models. However, little is know about the role of miRNAs in TGFß mediated fibrogenic gene regulation. By using miRNA qRT-PCR array, we have identified miRNAs whose expression are regulated by TGFß in IMR-90 cells. Among those down-regulated miRNAs are miR-29 family members. Knockdown miR-29 in IMR-90 cells results in up-regulation of a large number of extracellular matrix and fibrogenic genes including family members of collagen, laminin, integrin, ADAM and MMP, many of them are predicted or confirmed miR-29 targets. Hierarchichal clustering analysis of mRNA array data revealed that many extracellular matrix and fibrogenic genes up-regulated by TGFß in IMR-90 cells, are also up-regulated in miR-29 KD cells. Moreover, the similar set of extracellular matrix and fibrogenic genes is also significantly up-regulated in bleomycin treated mouse lungs. Together, our data strongly suggest that downstream of the TGFß, miR-29 is a master modulator of genes involved in extracellular matrix formation and might play a significant role in pulmonary fibrosis.
GSE18686 ImmunoHuman Psoriasis 58 7 To determine the transcriptional profile associated with macrophage polarization to M1 or M2, we cultured macrophages derived from monocytes for 7 days and treated them with IFNg, IL-4, TNF, LPS, and LPS+IFNg (n=7). Psoriasis lesional and non-lesional skin biopsies were included (n=5 pairs).
GSE18948 ImmunoHuman Psoriasis 16 1 Alefacept treatment is highly effective in a select group patients with moderate-to-severe psoriasis, and is an ideal candidate to develop systems to predict who will respond to therapy. A clinical trial of 22 patients with moderate to severe psoriasis treated with alefacept (7.5mg weekly i.v. x12 weeks) was conducted in 2002-2003, as a mechanism of action study. Patients were classified as responders or non-responders to alefacept based on histological criteria. Microarray data from PBMCs of 16 of these patients was analyzed to generate a treatment response classifier. We used a discriminant analysis method that performs sample classification from gene expression data, via nearest shrunken centroid method. A disease response classifier using 23 genes was created to accurately predict response to alefacept (12.3% error rate in favour of responders). This preliminary study may provide a useful tool to predict response of psoriatic patients with alefacept.
GSE18965 ImmunoHuman Asthma 16 1 Rationale: Damage to airway epithelium is followed by deposition of extracellular matrix (ECM) and migration of adjacent epithelial cells. We have shown that epithelial cells from asthmatic children fail to heal a wound in vitro. Objectives: To determine whether dysregulated ECM production by the epithelium plays a role in aberrant repair in asthma. Methods: Airway epithelial cells (AEC) from children with asthma (n=36), healthy atopic (n=23) and healthy non-atopic controls (n=53) were investigated by microarray, gene expression and silencing, transcript regulation analysis and ability to close mechanical wounds. Results: Wound repair of AEC from healthy and atopic children were not significantly different and were both faster than AEC from asthmatics. Microarray analysis revealed differential expression of multiple gene sets associated with repair and remodeling in asthmatic AEC. Fibronectin (FN) was the only ECM component whose expression was significantly lower in asthmatic AEC. Expression differences were verified by qPCR and ELISA, and reduced FN expression persisted in asthmatic cells over passage. Silencing of FN expression in non-asthmatic AEC inhibited wound repair, while addition of FN to asthmatic AEC restored reparative capacity. Asthmatic AEC failed to synthesize FN in response to wounding or cytokine/growth factor stimulation. Exposure to 5’, 2’deoxyazacytidine had no effect on FN expression and subsequent analysis of the FN promoter did not show evidence of DNA methylation. Conclusions: These data show that the reduced capacity of asthmatic epithelial cells to secrete FN is an important contributor to the dysregulated AEC repair observed in these cells.
GSE19060 ImmunoHuman Arthritis 8 1 Menisci play a vital role in load transmission, shock absorption and joint stability. The current dogma is that the menisci simply protects the cartilage and play no role in osteoarthritis (OA) unless they are injured. However, there is increasing evidence suggesting that OA menisci may not merely be bystanders in the disease process of OA. This study sought: 1) to determine the prevalence of meniscal degeneration in OA patients, 2) to examine gene expression in OA meniscal cells compared to normal control meniscal cells, and 3) to test the hypothesis that OA meniscal cells are different from normal meniscal cells.\r\nThe grades of meniscal degeneration correlated in a positive fashion with the grades of articular cartilage degeneration (r = 0.672; P < 0.0001). Many genes classified in the biological processes of immune response, inflammatory response, biomineral formation and cell proliferation, including major histocompatibility complex, class II, DP alpha 1 (HLA-DPA1), integrin, beta 2 (ITGB2), ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), ankylosis, progressive homolog (ANKH) and fibroblast growth factor 7 (FGF7), were expressed at higher levels compared to normal control meniscal cells. In addition, many genes that were previously implicated in OA were also expressed at higher levels in OA meniscal cells, including ADAM metallopeptidase with thrombospondin type 1 motif, 5 (ADAMTS5). Our findings suggest that OA is a whole joint disease. Meniscal cells may play an active role in the development of OA. Investigation of the gene expression profiles of OA meniscal cells may reveal new therapeutic targets for OA therapy and also may uncover novel disease markers for early diagnosis of OA.
GSE19182 ImmunoHuman Asthma 21 5 Background: In asthma, airway epithelium remodeling can already be detected during childhood, and epithelial cells are more susceptible to virus and oxidative stress. Their exact role in natural history and severity of children allergic respiratory disease remains however surprisingly unexplored.\r\nAim: To analyze dysfunctions of epithelium in dust mite allergic respiratory disease (rhinitis ± asthma) in children.\r\nMethods: Expression profilings of nasal epithelial cells collected by brushing were performed on Affymetrix Hugene 1.0 ST arrays. All allergic patients were sensitized to dust mite. 19 patients had an isolated allergic rhinitis (AR). 14 patients had AR associated with asthma. Patients were compared to 12 controls, their severity and control being assessed according to NAEPP and ARIA criteria. Infections by respiratory viruses were excluded by real-time PCR measurements.\r\nResults: 61 probes were able to distinguish allergic rhinitis children from healthy controls. A majority of these probes was under the control of Th2 cytokines, as evidenced by parallel experiments performed on primary cultures of nasal epithelial cells. In uncontrolled asthmatic patients, we observed not only an enhanced expression of these Th2-responsive transcripts, but also a down-regulation of interferon-responsive genes.\r\nConclusion: Our study identifies a Th2 driven epithelial phenotype common to all dust mite allergic children. Besides, it suggests that epithelium is involved in the severity of the disease. Expression profiles observed in uncontrolled asthmatic patients suggest that severity of asthma is linked at the same time to atopy and to impaired viral response.\r\nDifferentiated HNECs gene expression profiling in context of Th2 and IFN cytokine stimulation
GSE19187 ImmunoHuman Asthma 38 2 Background: In asthma, airway epithelium remodeling can already be detected during childhood, and epithelial cells are more susceptible to virus and oxidative stress. Their exact role in natural history and severity of children allergic respiratory disease remains however surprisingly unexplored.\r\nAim: To analyze dysfunctions of epithelium in dust mite allergic respiratory disease (rhinitis ± asthma) in children.\r\nMethods: Expression profilings of nasal epithelial cells collected by brushing were performed on Affymetrix Hugene 1.0 ST arrays. All allergic patients were sensitized to dust mite. 19 patients had an isolated allergic rhinitis (AR). 14 patients had AR associated with asthma. Patients were compared to 12 controls, their severity and control being assessed according to NAEPP and ARIA criteria. Infections by respiratory viruses were excluded by real-time PCR measurements.\r\nResults: 61 probes were able to distinguish allergic rhinitis children from healthy controls. A majority of these probes was under the control of Th2 cytokines, as evidenced by parallel experiments performed on primary cultures of nasal epithelial cells. In uncontrolled asthmatic patients, we observed not only an enhanced expression of these Th2-responsive transcripts, but also a down-regulation of interferon-responsive genes.\r\nConclusion: Our study identifies a Th2 driven epithelial phenotype common to all dust mite allergic children. Besides, it suggests that epithelium is involved in the severity of the disease. Expression profiles observed in uncontrolled asthmatic patients suggest that severity of asthma is linked at the same time to atopy and to impaired viral response.\r\nNasal epithelium gene expression profiling of dust mite allergic children with isolated rhinitis, rhinitis associated with asthma and controls.
GSE1919 ImmunoHuman Arthritis 15 2 Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease of unknown etiology and pronounced inter-patient heterogeneity. To characterize RA at the molecular level and to uncover key pathomechanisms, we performed whole-genome gene expression analyses. Synovial tissues from rheumatoid arthritis patients were compared to those from osteoarthritis patients and to normal donors.
GSE19224 ImmunoHuman 2015Q2 28 1 paired comparison of RNA expression in peripheral blood mononuclear cells in the same group of 14 multiple sclerosis patients while stable and while in relapse.\r\nA defining feature of multiple sclerosis is the occurrence of clinical relapses separated by periods of clinical stability. Better understanding of the events underlying clinical relapse might suggest new approaches to treatment. We used microarrays to measure mRNA expression in the peripheral blood of 14 MS patients during clinical relapse and while stable. Seventy-one transcripts changed expression at the p<0.001 significance level. The most notable finding was decreased expression of transcripts with regulatory function, expressed primarily in non-T cells. Transcripts with increased expression were primarily expressed in T cells. Pathways analysis suggested involvement of the cytokine network, coagulation and complement cascades, IL-10 signaling, and NF-?B signaling.
GSE19285 ImmunoHuman 2015Q2 144 4 The purpose of this study was to characterize the transcriptional effects induced by intramuscular IFN-beta-1a treatment (Avonex, 30 µg once weekly) in patients with relapsing-remitting form of multiple sclerosis (MS). By using Affymetrix DNA microarrays, we obtained genome-wide expression profiles of peripheral blood mononuclear cells from 24 MS patients within the first four weeks of IFN-beta administration.
GSE19301 ImmunoHuman Asthma 685 2 A large, prospective, non-interventional study was designed to study gene expression changes in peripheral blood mononuclear cells (PBMCs) associated with asthma exacerbations over the course of a year. PBMC samples were collected from subjects at the time of the study visits defined as 1) Quiet: during stable disease at 3 month intervals, 2) Exacerbation: during a 14 day period of deteriorating asthma and 3) Follow-up: within 14 days after cessation of an exacerbation. Gene expression levels during stable asthma, exacerbation, and two weeks after an exacerbation were compared.
GSE19314 ImmunoHuman LungDisease 66 3 We hypothesized that microarray analyses of whole blood gene expression would identify patterns of gene expression useful in the diagnosis for sacroidosis and identify inflammatory mediators relevant to the underlying pathophysiology.
GSE19332 ImmunoHuman ALS 10 1 Gene expression profiling has been performed on motor cortex and spinal cord homogenates and of sporadic ALS cases and controls, to identify genes and pathways differentially expressed in ALS. More recent studies have combined the use of laser capture microdissection (LCM) with gene expression profiling to isolate the motor neurons from the surrounding cells, such as microglia and astrocytes, in order to determine those genes differentially expressed in the vulnerable cell population – i.e. motor neuron.
GSE19392 ImmunoHuman nomodel 169 0 We defined the major transcriptional responses in primary human bronchial epithelial cells (HBECs) after either infection with influenza or treatment with relevant ligands. We used four different strategies, each highlighting distinct aspects of the response. (1) cells were infected with the wild-type PR8 influenza virus that can mount a complete replicative cycle. (2) cells were transfected with viral RNA (‘vRNA’) isolated from influenza particles. This does not result in the production of viral proteins or particles and identifies the effect of RNA-sensing pathways (e.g., RIG-I.). (3) Cells were treated with interferon beta (IFNb), to distinguish the portion of the response which is mediated through Type I IFNs. (4) Cells were infected with a PR8 virus lacking the NS1 gene (‘DNS1’). The NS1 protein normally inhibits vRNA- or IFNb-induced pathways, and its deletion can reveal an expanded response to infection.
GSE19407 ImmunoHuman COPD 127 2 The Wnt pathway plays a central role in controlling differentiation of epithelial tissues; when Wnt is on, differentiation is suppressed, but when Wnt is off, differentiation is allowed to proceed. Based on this concept, we hypothesized that expression of key genes in the Wnt pathway are suppressed in the human airway epithelium under the stress of cigarette smoking, a stress associated with dysregulation of the differentiated state of the airway epithelium. For this purpose, HG-U133 Plus 2.0 microarrays were used to assess the expression of Wnt-related genes in the small airway (10th-12th generation) epithelium (SAE) obtained via bronchoscopy and brushing of healthy nonsmokers (n=47), healthy smokers (n=58), and smokers with established COPD (n=22). With expression defined as present in >20% of samples, microarray analysis demonstrated that 35 of 57 known Wnt-related genes are expressed in the adult SAE. Wnt pathway downstream targets ß-catenin (p<0.05) and the transcription factor 7-like 1 were down-regulated in healthy smokers, and smokers with COPD, as were a number of Wnt target genes, including VEGFA, CCND1, MMP7, CLDN1, SOX9, RHOU (all p<0.05 compared to healthy nonsmokers). As a mechanism to explain this broad, smoking-induced suppression of the Wnt pathway, we assessed expression of the DKK and SFRP families, extracellular regulators that suppress the Wnt pathway. Among these, secreted frizzled-related protein 2 (SFRP2), was up-regulated 4.3-fold (p<0.0001) in healthy smokers and 4.9-fold (p<0.0001) in COPD smokers, an observation confirmed by TaqMan Real-time PCR. AT the protein levels, Western analysis demonstrated SFRP2 up-regulation, and immunohistochemistry demonstrated that the smoking-induced SFRP2 upregulation occurred in differentiated ciliated cells. Finally, cigarette smoke extract mediated up-regulation of SFRP2 and downregulation of Wnt target genes in airway epithelial cells in vitro. These observations are consistent with the hypothesis that the Wnt pathway plays a role in airway epithelial cell differentiation in the adult human airway epithelium, with smoking associated with down-regulation of Wnt pathway, contributing to the dysregulation of airway epithelial differentiation observed in the smoking-related airway disorders.
GSE19519 ImmunoHuman ALS 224 2 The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) results in the condition called “ER stress” which induces the unfolded protein response (UPR) which is a complex cellular process that includes changes in expression of many genes. Failure to restore homeostasis in the ER is associated with human diseases. To identify the underlying changes in gene expression in response to ER stress, we induced ER stress in human B-cells and then measured gene expression at 10 time-points. We followed up those results by studying cells from 60 unrelated people. We rediscovered genes that were known to play a role in ER stress response and uncovered several thousand genes that are not known to be involved. Two of these are VLDLR and INHBE which showed significant increase in expression following ER stress in B-cells and\r\nin primary fibroblasts. To study the links between unfolded protein response and disease susceptibility, we identified ER stress responsive genes that are associated with human diseases and assessed individual differences in ER stress response. Many of the UPR genes are associated with Mendelian disorders such as Wolfram syndrome and complex\r\nhuman diseases including amyotrophic lateral sclerosis and diabetes. Data from two independent samples showed extensive individual variability in ER stress response. Additional analyses with monozygotic twins revealed significant correlations within twin pairs in their responses to ER stress thus showing evidence for heritable variation among individuals. These results have implications for basic understanding of ER function and its role in disease susceptibility.
GSE19664 ImmunoHuman Arthritis 8 1 The recruitment of mesenchymal stem cells in order to reconstruct damaged cartilage of osteoarthritis joints is a challenging tissue engineering task. Vision towards this goal is blurred by a lack of knowledge about the underlying differences between chondrocytes and MSC during the chondrogenic cultivation process. The aim of this study was to shed light on the differences between chondrocytes and MSC occurring during chondral differentiation through tissue engineering.\r\nAs a model we used the pellet culture system under chondrogenic conditions for the comparison of chondrocyte and MSC differentiation. Immunohistology was followed by microarray analysis, which was filtered through already published datasets describing different developmental processes. Validation was performed with quantitative RT-PCR.\r\nResults describe inferior chondrogenic ECM-production by MSCs and underline their closer link to the osteogenic lineage. Chondrocytes have an upregulated fatty acid/cholesterol metabolism which might give hints for future modifications of culture conditions.
GSE19667 ImmunoHuman COPD 121 0 Background: Healthy individuals exposed to low levels of cigarette smoke have a decrement in lung function and higher risk for lung disease compared to unexposed individuals. We hypothesized that healthy individuals exposed to low levels of tobacco smoke must have biologic changes in the small airway epithelium compared to healthy unexposed individuals. Methods: Small airway epithelium was obtained by bronchoscopy from 121 individuals; microarrays assessed genome wide gene expression, and urine nicotine and cotinine were used to categorized subjects as “nonsmokers,” “active smokers,” and “low exposure.” The gene expression data was used to determine the threshold and ID50 of urine nicotine and cotinine at which the small airway epithelium showed abnormal responses. Results: There was no threshold of urine nicotine without an abnormal small airway epithelial response, and only a slightly above detectable threshold abnormal response for cotinine. The nicotine ID50 for nicotine was 25 ng/ml and cotinine 104 ng/ml. Conclusions: The small airway epithelium detects and responds to low levels of tobacco smoke with transcriptome modifications. This provides biologic correlates of epidemiologic studies linking low level tobacco smoke exposure to lung health risk, health, identifies genes in the lung cells most sensitive to tobacco smoke and defines thresholds at the lung epithelium responds to inhaled tobacco smoke.
GSE19903 ImmunoHuman Asthma 20 1 Asthma exacerbations are associated with subsequent deficits in lung function.\r\nHere, we tested the hypothesis that a specific pattern of inflammatory responses during acute exacerbations may be associated with susceptibility to chronic airway obstruction.
GSE19976 ImmunoHuman PulmonaryFibrosis 15 1 Approximately 60-70% of patients with pulmonary sarcoidosis have a good outcome, with disease that resolves spontaneously. It is unclear why some patients progress to fibrotic disease, and there is currently no marker that differentiates these patients from those with self-limiting lung disease.\r\nUsing the Affymetrix Human Gene 1.0 ST Array, we examined gene expression in lung tissue samples obtained using bronchoscopic transbronchial biopsy from 8 patients with active but self-limiting pulmonary sarcoidosis and 7 with active, progressive, fibrotic pulmonary disease. Analyses were performed to identify differentially expressed genes between the two groups, and to test for enrichment of sets of genes associated with defined biological processes from the Gene Ontology Consortium, as well as with gene sets derived from published data for idiopathic pulmonary fibrosis (IPF) and hypersensitivity pneumonitis (HP).
GSE20098 ImmunoHuman Arthritis 173 3 An exploration of the peripheral blood CD4+ T-cell transcriptome of early arthritis clinic attendees, seeking novel diagnostic tools and pathophysiological insights.
GSE20153 ImmunoHuman PD 16 1 Genome-wide transcriptome analysis of expression changes in EBV transformed cell lines from the Coriell Cell Repository in Parkinson and Control subjects.
GSE20163 ImmunoHuman PD 17 1 Systematic meta-analysis and replication of genome-wide expression studies identifies molecular pathways of Parkinson's disease.\r\nExamination of substantia nigra from postmortem brains of 8 patients with Parkinson's disease (PD).
GSE20164 ImmunoHuman PD 11 1 Systematic meta-analysis and replication of genome-wide expression studies identifies molecular pathways of Parkinson's disease.\r\nAnalysis of substantia nigrae from postmortem brains of 6 patients with Parkinson's disease (PD). Results provide insight into the molecular processes perturbed in the PD substantia nigra.
GSE20168 ImmunoHuman PD 29 1 Post mortem tissue was dissected from two groups of age and gender matched groups of Parkinson and Control subjects
GSE20257 ImmunoHuman COPD 135 2 The apical junctional complex (AJC), composed of tight junctions and adherens junctions, is essential for maintaining epithelial barrier function. Since cigarette smoking and chronic obstructive pulmonary disease (COPD), the major smoking-induced disease, are both associated with increased lung epithelial permeability, we hypothesized that smoking alters the transcriptional program regulating AJC integrity in the small airway epithelium (SAE), the primary site of pathological changes in COPD. Transcriptome analysis revealed a global down-regulation of physiological AJC gene expression in the SAE of healthy smokers (n=53) compared to healthy nonsmokers (n=59), an observation associated with changes in molecular pathways regulating epithelial differentiation such as PTEN signaling and accompanied by induction of cancer-related AJC genes. Genome-wide co-expression analysis identified a smoking-sensitive AJC transcriptional network. The overall expression of AJC-associated genes was further decreased in COPD smokers (n=23). Exposure of human airway epithelial cells to cigarette smoke extract in vitro resulted in down-regulation of several AJC-related genes, accompanied by decreased transepithelial resistance. Thus, cigarette smoking alters the AJC gene expression architecture in the human airway epithelium, providing a molecular basis for the dysregulation of airway epithelial barrier function during the development of smoking-induced lung disease.
GSE20264 ImmunoHuman Psoriasis 7 1 Background: Previous work has identified CD11c+CD1c- dendritic cells (DCs) as the major ”inflammatory” dermal DC population in psoriasis vulgaris and CD1c+ DCs as the “resident” cutaneous DC population. Objective: To further define molecular differences between these two myeloid dermal DC populations. Methods: Inflammatory and resident DCs were single-cell sorted from psoriasis lesional skin biopsies, and gene array expression profiling was performed. Results were confirmed with RT-PCR, flow cytometry, immunohistochemistry, and double label immunofluorescence. Pooled human keratinocytes were cultured for functional studies. Results: TNF-related apoptosis-inducing ligand (TRAIL), Toll-like receptors (TLRs) 1 and 2, S100A12/EN-RAGE, CD32, and many other inflammatory products were selectively expressed in inflammatory DCs than in resident DCs. Flow cytometry and immunofluorescence confirmed higher protein expression on CD1c- versus CD1c+ DCs. TRAIL receptor, death receptor 4 (DR4), was expressed on basal keratinocytes and blood vessels, and in vitro culture of keratinocytes with rh-TRAIL induced CCL20 leukocyte chemokine. Conclusion: CD11c+CD1c- inflammatory DCs in psoriatic lesional skin express a wide range of inflammatory molecules compared to skin resident CD1c+ DCs. Some molecules made by inflammatory DCs, including TRAIL, could have direct effects on keratinocytes or other skin cell types to promote disease pathogenesis.
GSE20291 ImmunoHuman PD 35 1 Post mortem tissue was dissected from two groups of age and gender matched groups of Parkinson and Control subjects
GSE20292 ImmunoHuman PD 29 1 Post mortem tissue was dissected from two groups of age and gender matched groups of Parkinson and Control subjects
GSE20307 ImmunoHuman Arthritis 160 3 Objective. To identify gene expression differences in peripheral blood from patients with early and late onset juvenile idiopathic arthritis (JIA).\r\nMethods. Peripheral blood mononuclear cells (PBMC) were isolated from 56 healthy controls and 104 patients with recent onset JIA (39 persistent oligoarticular, 45 RF-polyarticular, and 20 systemic). Poly(A) RNA was amplified and labeled using NuGEN Ovation, and gene expression assessed with Affymetrix HG-U133 Plus 2.0 GeneChips®.\r\nResults. A total of 832 probe sets revealed gene expression differences (false-discovery rate 5%) in PBMC from children with oligoarticular JIA whose disease began before 6 years of age (age at onset [AaO] <6; early onset), compared to subjects whose disease began at 6 years of age or later (AaO ≥6; late onset). In early onset patients there was greater expression of genes related to B-cells, and lesser expression of genes related to cells of the myeloid lineage. Support Vector Machine algorithms identified samples from early or late onset oligoarticular (97% accuracy) or polyarticular (89% accuracy) JIA patients, but not systemic JIA patients or healthy controls. Principal component analysis showed that the major classifier of samples was AaO regardless of whether they had oligoarticular or polyarticular JIA.\r\nConclusion. PBMC gene expression analysis reveals biologic differences between early and late onset JIA patients independent of classification based on the number of joints involved. These data suggest AaO may be an important parameter to consider in JIA classification. Furthermore, different pathologic mechanisms may influence AaO, and understanding these processes may lead to improved treatment of JIA.
GSE20589 ImmunoHuman ALS 10 1 Gene expression profiling has been performed previously on motor cortex and spinal cord homogenates and of sporadic ALS cases and controls, to identify genes and pathways differentially expressed in ALS. More recent studies have combined the use of laser capture microdissection (LCM) with gene expression profiling to isolate the motor neurons from the surrounding cells, such as microglia and astrocytes, in order to determine those genes differentially expressed in the vulnerable cell population – i.e. motor neuron.\r\nThe aim of the present study is to combine LCM and microarray analysis to determine those genes and pathways differentially expressed in MNs from human SOD1-related MND and to establish potential pathways for therapeutic intervention.
GSE20690 ImmunoHuman Arthritis 68 1 Introduction of biologics, such as infliximab, to the therapy of rheumatoid arthritis (RA) patients has revolutionized the treatment of this disease. However, biomarkers for predicting the efficacy of the drug at an early phase of treatment for selecting real responders have not been found. We here present predictive markers based on a thorough transcriptome analysis of white blood cells from RA patients. RNA from whole blood cells of consecutive 42 patients before the first infusion was analyzed with microarrays for training studies. Samples from the subsequent 26 consecutive patients were used for a prospective study. We categorized the results into no inflammation and residual inflammation groups using the serum C-reactive protein (CRP) level at 14 weeks after the first infusion. The accuracy of prediction in our study was 65.4%.
GSE21231 ImmunoHuman IBD 40 1 Although corticosteroids remain a mainstay of therapy for UC, a meta-regression of cohort studies in acute severe ulcerative colitis (UC) showed that 29% of patients fail corticosteroid therapy and require escalation of medical management or colectomy.\r\nWe aimed to determine whether genes expressed in whole blood early following initiation of intravenous corticosteroid treatment can be associated with response.
GSE2125 ImmunoHuman Asthma 45 1 This series represents isolated alveolar macrophages from human subjects.
GSE21369 ImmunoHuman PulmonaryFibrosis 29 5 The mechanisms and molecular pathways underlying interstitial lung diseases (ILDs) are poorly understood. Systems biology approaches were used to identify perturbed networks in these disease states to gain a better understanding of the underlying mechanisms of disease. Through profiling genes and miRNAs, we found subsets of genes and miRNAs that distinguish different disease stages, ILDs from controls, and idiopathic pulmonary fibrosis (IPF) from non-specific interstitial pneumonitis (NSIP). Traditional pathway analysis revealed several disease-associated modules involving genes from the TGF-beta, Wnt, focal adhesion and smooth muscle actin pathways that may be involved in advancing fibrosis.\r\nA comprehensively integrative approach was used to construct a global gene regulatory network based on the perturbation of key regulatory elements, transcriptional factors and miRNAs. The data also demonstrated that several subnetworks were significantly associated with key molecules involved in the diseases. We present a broad overview of the disease at a molecular level and discuss several possibly key regulatory molecular circuits that could play central roles in facilitating the progression of ILDs.
GSE21411 ImmunoHuman LungDisease 29 0 This SuperSeries is composed of the SubSeries listed below.
GSE21450 ImmunoHuman AD 20 2 Mitochondrial dysfunction has been directly or indirectly implicated in the pathogenesis of a number of neurodegenerative disorders including Parkinson's disease, Alzheimer's disease and Amyotrophic Lateral Sclerosis (ALS). We used exon-sentive microarrays to characterize the responses to different mitochondrial perturbations in cellular models. We examined human SH-SY5Y neuroblastoma cells treated with paraquat, a neurotoxic herbicide which both catalyzes the formation of reactive oxygen species (ROS) and induces mitochondrial damage in animal models, and SH-SY5Y cells stably expressing the mutant SOD1(G93A) protein, one of the genetic causes of ALS. We identified a common set of genes that have a deregulated transcription and alternative splicing in both models. Noticeably, pathway analysis revealed that the expression of a subset of genes involved in neuritogenesis and axon guidance is perturbed, suggesting that alterations of axonal function may descend directly from mitochondrial damage and be responsible for neurodegenerative conditions.\r\nThis SuperSeries is composed of the SubSeries listed below.
GSE21521 ImmunoHuman Arthritis 154 7 Objective. Previous observations suggest that active systemic juvenile idiopathic arthritis (sJIA) is associated with a prominent erythropoiesis gene expression signature. The aim of this study was to determine the association of this signature with peripheral blood mononuclear cell (PBMC) subpopulations and its specificity for sJIA as compared to related conditions.\r\n125 patients with JIA (18 sJIA and 107 non-sJIA) and 29 controls were studied. PBMC were isolated and analyzed for multiple surface antigens by flow cytometry and for gene expression profiles. The proportions of different PBMC subpopulations were compared among sJIA, non-sJIA patients and controls and subsequently correlated with the strength of the erythropoiesis signature. Additional gene expression data from patients with familial hemophagocytic lymphohistiocytosis (FHLH) and from a published sJIA cohort were analyzed to determine if the erythropoiesis signature was present.
GSE21802 ImmunoHuman 2015Q2 40 3 Critical disease caused by the new 2009 pandemic influenza virus (nvH1N1) is a challenge for physicians and scientist. As evidenced in SARS and H5N1, the development of an effective immune response plays a key role to overcome viral diseases. We studied host`s gene expression signatures, cytokine and antibody responses along the first week of hospitalization in 19 critically ill patients with primary nvH1N1 pneumonia and two degrees of respiratory involvement. Presence of comorbidities and absence of immunosuppresory conditions were the common antecedents in both groups. The most severe patients (n=12) showed persistant respiratory viral secretion, increased levels of pro-inflammatory cytokines and chemokines in serum, and elevated systemic levels of two immunosuppresory cytokines (IL-10 and IL-1ra). Both groups were able to produce specific antibodies against the virus. The average day for antibody production was day 9 in the course of the disease, defining an early period of innate immunity and a late period of adaptive immunity. The most severe group evidenced a poor expression of a set of MHC class II and T cell receptor (TCR) related genes participating in antigen presentation and cell mediated immune responses in the late phase. 7 patients of this group finally died. This findings evidence that, as observed in sepsis, severe H1N1 disease course with immunoparalysis, which could explain the poor control of the virus along with the increased incidence of bacterial superinfection observed in these patients.
GSE21942 ImmunoHuman 2015Q2 29 1 Multiple sclerosis (MS) is a neurodegenerative disease with a presumed autoimmune component. Expression profiling in immune cells can therefore be used in order to identify genes and pathways involved in MS pathogenesis.\r\nWe conducted a genome-wide expression study in peripheral blood mononuclear cells (PBMC) from 12 MS patients and 15 controls in order to identify differentially expressed genes and pathways in MS.
GSE21959 ImmunoHuman Arthritis 36 2 Inflammatory tissues are characterized by low oxigen concentrations (hypoxia). These conditions are very different from that usually present in tissue cultures where transcriptomic profiles of human fibroblasts from inflammatory tissues have been previously analysed. The aim of this study was to characterize the changes on gene expression induced by hypoxia in human synovial fibroblasts. We used microarray expression profiling in paired normoxic and hypoxic cultures of healthy and rheumatoid arthritis (RA) synovial fibroblasts (HSF and RASF). Hypoxia induces significant changes on the expression of large groups of genes in both HSF and RASF. The hypoxic and normoxic profiles are also different between both groups. These data demonstrate that hypoxia induces significant changes on gene expression in HSF and RASF and identify differences between RASF and HSF.
GSE22047 ImmunoHuman COPD 230 3 Cystatin A (gene: CSTA), is up-regulated in non-small-cell lung cancer (NSCLC) and dysplastic vs normal human bronchial epithelium. In the context that chronic obstructive pulmonary disease (COPD), a small airway epithelium (SAE) disorder, is independently associated with NSCLC (especially squamous cell carcinoma, SCC), but only occurs in a subset of smokers, we hypothesized that genetic variation, smoking and COPD modulate CSTA gene expression levels in SAE, with further up-regulation in SCC. Gene expression was assessed by microarray in SAE of 178 individuals [healthy nonsmokers (n=60), healthy smokers (n=82), and COPD smokers (n=36)], with corresponding large airway epithelium (LAE) data in a subset (n=52). Blood DNA was genotyped by SNP microarray. Twelve SNPs upstream of the CSTA gene were all significantly associated with CSTA SAE gene expression (p<0.04 to 5 x 10-4). CSTA gene expression levels in SAE were higher in COPD smokers (28.4 ± 2.0) than healthy smokers (19.9 ± 1.4, p<10-3), who in turn had higher levels than nonsmokers (16.1 ± 1.1, p<0.04). CSTA LAE gene expression was also smoking-responsive (p<10-3). Using comparable publicly available NSCLC expression data, CSTA was up-regulated in SCC vs LAE (p<10-2) and down-regulated in adenocarcinoma vs SAE (p<10-7). All phenotypes were associated with significantly different proportional gene expression of CSTA to cathepsins. The data demonstrate that regulation of CSTA expression in human airway epithelium is influenced by genetic variability, smoking, and COPD, and is further up-regulated in SCC, all of which should be taken into account when considering the role of CSTA in NSCLC pathogenesis.
GSE22148 ImmunoHuman COPD 143 2 Induced sputum is used to sample inflammatory cells, predominantly neutrophils and macrophages, from the airways of COPD patients. Our aim was to identify candidate genes associated with the degree of airflow obstruction and the extent of emphysema by expression profiling, and then to confirm these findings for selected candidates using specific PCR and protein analysis.
GSE22212 ImmunoHuman 2015Q2 5 1 The pathogenesis of avian influenza A H5N1 virus in human has not been clearly elucidated. There have been increasing evidence suggesting a role for virus-induced cytokine dysregulation in contributing to the pathogenesis of human H5N1 disease. However, the role of aberrant innate immune response in human lungs infected by avian influenza H5N1 virus has not been explored and direct evidence for inappropriate innate responses in lungs of avian influenza H5N1 virus infected patients is lacking.
GSE22324 ImmunoHuman nomodel 200 0 Analysis of expression quantitative trait loci (eQTLs) using RNA derived from freshly harvested peripheral blood CD4+ lymphocytes from 200 asthmatics collected in clinical settings.
GSE22356 ImmunoHuman SystemicSclerosis 38 3 Rationale: Pulmonary arterial hypertension is a common and potentially fatal complication of scleroderma that may involve inflammatory and autoimmune mechanisms. Alterations in the gene expression of peripheral blood mononuclear cells have been previously described in patients with pulmonary arterial hypertension. The ability to identify patients at risk for developing pulmonary hypertension would be clinically beneficial.\r\nObjective: To identify genes that are differentially expressed in peripheral blood mononuclear cells in scleroderma patients with and without pulmonary hypertension which could be used as biomarkers of disease for early diagnosis and provide insight into pathogenesis of pulmonary hypertension in at-risk populations.\r\nMethods and Results: Gene expression analysis was performed on a carefully characterized Microarray Cohort of scleroderma patients with (n=10) and without (n=10) pulmonary hypertension. Differentially expressed genes were confirmed in the Microarray Cohort and validated in a separate Validation Cohort of scleroderma patients with (n=15) and without (n=19) pulmonary hypertension by RT-qPCR. We identified inflammatory and immune-related genes including interleukin-7 receptor (IL-7R) and chemokine receptor 7 (CCR7) as differentially expressed in patients with scleroderma-associated pulmonary hypertension. Flow cytometry confirmed decreased expression of IL-7R on circulating CD4+ T cells from scleroderma patients with pulmonary hypertension.\r\nConclusions: Differences exist in the expression of inflammatory and immune-related genes in peripheral blood cells derived from patients with scleroderma-related pulmonary hypertension compared to those with normal pulmonary artery pressures. These findings may have implications as biomarkers to screen at-risk populations to facilitate early diagnosis and provide insight into inflammatory and autoimmune mechanisms of scleroderma-related pulmonary hypertension.
GSE22528 ImmunoHuman Asthma 10 1 The implication of alveolar macrophages (AM) in asthma, a Th2 disease, has not been well characterized. Thus, the goal of this study is to better characterize AM phenotype of allergic asthmatic compared with normal subjects using genomic expression analyses. Microarray analyses were performed with AM isolated from bronchoalveolar lavage. Robust multiarray analysis (RMA) normalization and Smyth’s moderated t test were used to select differentially expressed genes. Fifty differentially expressed genes were identified. Nineteen have been classified in categories linked to stress or immune responses and among them; nine are part of the heat shock protein (HSP) family. Difference of expression for three (HSPD1, PRNP, SERPINH1) of the five selected genes were validated using real-time reverse transcription–polymerase chain reaction. Enzyme linked immunosorbent assay was used to measure the protein level of heat shock protein 60 (HSP60), the protein encoded by HSPD1, and showed difference in AM protein level between allergic asthmatic and control subjects. In summary, this study suggests that HSP gene family, particularly HSP60, is involved in AM functions in a context of allergic asthma. These results also support the involvement of AM immune functions in the development of an allergic asthmatic response.
GSE22619 ImmunoHuman IBD 20 1 Background and aims. The etiopathology of inflammatory bowel diseases is still poorly understood. To date, only few little data are available on the microbiota composition in ulcerative colitis (UC), representing a major subform of inflammatory bowel diseases. Currently, one of the main challenges is to unravel the interactions between genetics and environmental factors in the onset or during the progression and maintenance of the disease. The aim of the present study was to analyse twin pairs discordant for UC for both gut microbiota dysbiosis and host expression profiles at a mucosal level and to get insight into the functional genomic crosstalk between microbiota and mucosal epithelium in vivo. Methods. Biopsies were sampled from the sigmoid colon of both healthy and diseased siblings from UC discordant twin pairs but also from healthy twins. Microbiota profiles were assessed by 16S rDNA libraries while mRNA expression profiles were analysed from the same volunteers using Affymetrix microarrays.\r\nResults. UC patients showed a dysbiotic microbiota with lower diversity and more species belonging to Actinobacteria and Proteobacteria phyla. On the contrary, their healthy siblings’ microbiota contained more bacteria from the Lachnospiracea and Ruminococcaceae family than did healthy individuals . Sixty-three host transcripts significantly correlated with bacterial genera in healthy individuals whereas only 43 and 32 correlated with bacteria in healthy and UC siblings from discordant pairs, respectively. Several transcripts related to oxidative and immune responses were differentially expressed between unaffected and UC siblings. Conclusion. A loss of crosstalk between gut microbiota and host was highlighted in UC patients. This defect was also striking in healthy siblings from discordant pairs, as was the lower biodiversity within the microbiota. Our results suggest disease-relevant interactions between host transcriptome and microbiota. Moreover, unusual aerobic bacteria were noticed in UC mucosal microbiota, whereas healthy siblings from discordant pairs had higher percentages of potentially beneficialusual commensal bacterial species.
GSE22956 ImmunoHuman Arthritis 21 2 NFAT5 is an osmoprotective transcription factor whose DNA binding domain shares structural homology with NFkappaB and other member of NFAT family, but its role in chronic inflammatory diseases remains unclear. The mRNA profiling of synoviocytes and endothelial cells transfected with NFAT5-targeted siRNA reveals three major changes in cellular processes associated with the pathogenesis of rheumatoid arthritis: cell cycle and survival, angiogenesis, and cell migration.
GSE23073 ImmunoHuman NormalControl 27 7 CD14+ human monocytes differentiating into DCs in the presence of IL4 and GM-CSF were treated with agonists for RXR and its partners or vehicle 18 hours after plating (experiment with RXR and permissive partners, donor 1-3) or 14 hours after plating (experiment with nonpermissive partners, donor 4-6). Cells were harvested 12 hours thereafter. Experiments were performed in biological triplicates representing samples from three different donors.\r\nIn this study all probable RXR-signaling pathways induced by agonists for RXR, LXRs, PPARs, RAR and VDR were identified in differentiating human monocyte-derived dendritic cells.
GSE23203 ImmunoHuman SLE 34 4 Systemic lupus erythematosus (SLE) is characterized by increased vascular risk due to premature atherosclerosis independent of traditional risk factors. We previously proposed that interferon-a plays a crucial role in premature vascular damage in SLE. IFN-a alters the balance between endothelial cell apoptosis and vascular repair mediated by endothelial progenitor cells (EPCs) and myeloid circulating angiogenic cells (CACs). Here we demonstrate that IFN-a promotes an antiangiogenic signature in SLE and control EPCs/CACs, characterized by transcriptional repression of IL-1a and ß, IL-1 receptor 1 and vascular endothelial growth factor A (VEGF-A) and upregulation of IL-1 receptor antagonist (IL-1RN) and the decoy receptor IL1-R2. IL-1ß promotes significant improvement in the functional capacity of lupus EPCs/CACs, therefore abrogating the deleterious effects of IFN-a.\r\nWe used microarrays to analyze the effect of IFNa on peripheral blood EPCs/CACs and on bone marrow EPCs exposed to proangiogenic stimulation.\r\nThis SuperSeries is composed of the SubSeries listed below.
GSE23205 ImmunoHuman 2015Q2 10 1 A genetic study of the PRF1 gene has shown association of several polymorphisms with multiple sclerosis (MS). Haplotype analysis identified risk haplotypes strongly associated with male patients having the primary-progressive form of MS (PPMS). Gene expression microarrays were performed in 10 male PPMS patients carrying the risk (n=6) and protective haplotypes (n=4) in order to identify pathways associated with the risk haplotypes. Pathway analysis revealed overrepresentation of the cell killing gene ontology category among down-regulated genes in patients carrying risk haplotypes compared with patients carrying protective haplotypes.
GSE23290 ImmunoHuman PD 14 2 LRRK2 mutations are the most common genetic cause of Parkinson’s disease (PD). We performed a whole-genome RNA profiling of putamen tissue from idiopathic PD (IPD), LRRK2-associated PD (G2019S mutation), neurologically healthy controls and one asymptomatic LRRK2 mutation carrier, by using the Genechip Human Exon 1.0-ST Array. The differentially expressed genes found in IPD revealed an alteration of biological pathways related to long term potentiation (LTP), GABA receptor signalling, and calcium signalling pathways, among others. These pathways are mainly related with cell signalling cascades and synaptic plasticity processes. They were also altered in the asymptomatic LRRK2 mutation carrier but not in the LRRK2-associated PD group. The expression changes seen in IPD might be attributed to an adaptive consequence of a dysfunction in the dopamine transmission. The lack of these altered molecular pathways in LRRK2-associated PD patients suggests that these cases could show a different molecular response to dopamine transmission impairment.
GSE23307 ImmunoHuman 2015Q2 6 1 Compared to primary human monocytes in whole blood cultures, few B cells activated STAT1 in response to stimulation of 2000 IU/ml IFN-beta for 45 minutes. Because activation of STAT1 leads to apoptosis induction, we tested the hypothesis that less pro-apoptotic genes are induced in B cells as compared to monocytes.\r\nManuscript titled: Major differences in the responses of primary human leukocyte subsets to IFN-beta.\r\nAbstract: Treatment of cell lines with type I IFNs activates the formation of ISGF3 (STAT1/STAT2/ IRF9), which induces the expression of many genes. To study this response in primary cells, we treated fresh human blood with IFN-beta and used flow cytometry to analyze phosphorylated STATs1, 3 and 5 in CD4+ and CD8+ T cells, B cells, and monocytes. The activation of STAT1 was remarkably different among these leukocyte subsets. In contrast to monocytes, CD4+ and CD8+ T cells, few B cells activated STAT1 in response to IFN-beta, a finding that could not be explained by decreased levels of IFNAR2 or STAT1 or enhanced levels of SOCS1 or relevant protein tyrosine phosphatases in B cells. Micro-array and real-time PCR analyses revealed the induction of STAT1-dependent pro-apoptotic mRNAs in monocytes but not in B cells. These data show that ISGF3 or STAT1 homodimers are not the main activators of gene expression in primary B cells of healthy humans. Notably, in B cells and especially in CD4+ T cells, IFN-beta activated STAT5 in addition to STAT3, with biological effects often opposite from those driven by activated STAT1. These data help to explain why IFN-beta increases the survival of primary human B cells and CD4+ T cells, but enhances the apoptosis of monocytes, and also to understand how leukocyte subsets are differentially affected by endogenous type I IFNs during viral or bacterial infections, and by type I IFN treatment of patients with multiple sclerosis, hepatitis or cancer.
GSE23352 ImmunoHuman nomodel 499 0 We profiled genome-wide gene expression in non-tumorous human lung tissues. The overall goal of this project is to improve our molecular understanding of various lung diseases including lung cancer and chronic obstructive pulmonary disease (COPD).
GSE23529 ImmunoHuman nomodel 405 0 We profiled genome-wide gene expression in non-tumorous human lung tissues. The overall goal of this project is to improve our molecular understanding of various lung diseases including lung cancer and chronic obstructive pulmonary disease (COPD).
GSE23545 ImmunoHuman nomodel 445 0 We profiled genome-wide gene expression in non-tumorous human lung tissues. The overall goal of this project is to improve our molecular understanding of various lung diseases including lung cancer and chronic obstructive pulmonary disease (COPD).
GSE23552 ImmunoHuman Asthma 39 2 Asthmatic chronic rhinosinusitis with nasal polyps (aCRSwNP) is a common disruptive eosinophilic disease. Therefore, we sought to identify gene expression changes in nasosinus inflamed mucosa and adjacent polyp tissue from subjects with aCRSwNP.
GSE23597 ImmunoHuman IBD 113 9 A gene expression profiling sub-study was conducted in which colonic biopsy samples were collected for RNA extraction and hybridization to microarrays from 48 patients with UC who were participating in ACT 1, a placebo-controlled study of infliximab. Gene expression profiles from infliximab responders were compared with those of baseline and infliximab non-responder samples.\r\nInfliximab had a significant effect on mRNA expression in treatment responders, with both infliximab dose and duration of treatment having an effect. Genes affected are primarily involved with inflammatory response, cell-mediated immune responses, and cell-to-cell signaling. Infliximab non-responders had a molecular phenotype that closely resembled that of untreated patients with UC. Unlike responders, non-responders do not effectively modulate TH1, TH2, and TH17 pathways. Gene expression can differentiate placebo and infliximab responders.
GSE23630 ImmunoHuman IBD 18 4 Background: In the last decade, much attention has been drawn to probiotic bacteria in the context of inflammatory bowel disease (IBD), since the potential of certain strains to attenuate inflammation was demonstrated in several animal experiments and clinical studies. Data in humans elucidating the molecular mechanism of probiotic action are still scarce. To this end, we used an organ culture system of human colon mucosa and investigated the gene expression profiles after treatment with different probiotic bacteria in phorbol 12-myristate 13-acetate (PMA)/ionomycin (IO)) stimulated samples using whole genome microarrays. Moreover, we analyzed changes occurring in the intestinal explants cultured for 8 hours when compared to fresh, directly frozen mucosa, in order to infer the suitability of the system to study an inflammatory stimulus and likely antiinflammatory responses. Results: Culturing intestinal colon fragments during 8 hours elicited differential gene expression in 283 genes, 229 upregulated and 54 downregulated. Upregulated genes were predominantly related to apoptosis, whereas downregulated genes encoded mitochondrial proteins. No specific enrichment of genes related to inflammation or immune response could be detected, confirming the suitability of the system to further study the inmunomodulatory/anti-inflammatory properties of Lactobacillus casei BL23 (BL23), L.plantarum 299v (LP299v) and L.plantarum 299v (A-) (LP299v (A-)), a mutant strain with reduced adhesive properties to enterocytes. Intestinal explants were stimulated with PMA/IO for 3 hours and subsequently incubated with probiotic bacteria for 4 h. ANOVA analysis (p = 0,01) revealed 205 differentially expressed genes between Control, PMA/IO (Inflamed), and the 3 bacterial treatments. Most importantly, a number of PMA/IO induced genes related to immune response and immune system process such as IL-2, IFN-?, IL17A and pro-inflammatory cytokines CXCL9 and CXCL11 were downregulated by BL23, LP299v and LP299v (A-). The behaviour of the three Lactobacillus strains was quite similar, although their presence induced differential expression of a small number of genes in a strain dependent manner. Conclusion: The human colon organ culture was found to be a suitable model for the study of inflammatory/anti-inflammatory stimuli, and therefore it constitutes a valuable tool to determine the inmunomodulatory effect of probiotic bacteria. The global transcriptional profile evoked by strains BL23, LP299v and LP299v (A-) in artificially inflamed tissue indicated a clear homeostasis restoring effect, including a decrease of the signals produced by activated T cells.
GSE23687 ImmunoHuman Arthritis 22 1 Gene expression on peripheral blood mononuclear cells (PBMC) from SPARKS CHARMS juvenile idiopathic arthritis (JIA) cohort pre and post methotrexate therapy. This is the first study to our knowledge, to evaluate gene expression profiles in children with JIA before and after MTX, and to analyze genetic variation in differentially expressed genes. We have identified a gene, which may contribute to genetic variability in MTX response in JIA.
GSE23741 ImmunoHuman SystemicSclerosis 12 3 PKC-d inhibition with the selective inhibitor, rottlerin, resulted in potent downregulation of type I collagen expression and production in normal human dermal fibroblasts and abrogated the exaggerated type I collagen production and expression in fibroblasts cultured from affected skin from patients with the fibrosing disorder, systemic sclerosis (SSc). To elucidate the mechanisms involved in the ability of PKC-d to regulate collagen production in fibroblasts, we examined the effects of PKC-d inhibition on the transcriptome of normal and SSc-derived human dermal fibroblasts.\r\nWe used microarrays to detail the effects of PKC-d inhibition with rottlerin on the transcriptome of normal and SSc-derived human dermal fibroblasts and to identify gene networks that might be involved in the regulation of extracellular matrix by PKC-d.
GSE23832 ImmunoHuman 2015Q2 12 1 Affymetrix GeneChip Human Gene 1.0 ST Array was applied to compare the expression profiles in peripheral blood mononuclear cells(PBMC) between healthy controls and multiple sclerosis patients(MS pt).\r\nIt suggested that certain genes involved in apoptosis pathway have been changed regulated in PBMC from MS pt.
GSE24206 ImmunoHuman PulmonaryFibrosis 23 2 Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing lung disease that is difficult to diagnose and follows an unpredictable clinical course. The object of this study was to develop a predictive gene signature model of IPF from whole lung tissue. We collected whole lung samples from 11 IPF patients undergoing diagnostic surgical biopsy or transplantation. Whenever possible, samples were obtained from different lobes. Normals consisted of healthy organs donated for transplantation. We measured gene expression on microarrays. Data were analyzed by hierarchical clustering and Principal Component Analysis. By this approach, we found that gene expression was similar in the upper and lower lobes of individuals with IPF. We also found that biopsied and explanted specimens contained different patterns of gene expression; therefore, we analyzed biopsies and explants separately. Signatures were derived by fitting top genes to a Bayesian probit regression model. We developed a 153-gene signature that discriminates IPF biopsies from normal. We also developed a 70-gene signature that discriminates IPF explants from normal. Both signatures were validated on an independent cohort. The IPF Biopsy signature correctly diagnosed 76% of the validation cases (p < 0.01), while IPF Explant correctly diagnosed 78% (p < 0.001). Examination of differentially expressed genes revealed partial overlap between IPF Biopsy and IPF Explant and almost no overlap with previously reported IPF gene lists. However, several overlapping genes may provide a basis for developing therapeutic targets.
GSE24345 ImmunoHuman AD 6 1 To characterize mechanisms responsible for the CNS dopamine deficiency and the resulting neuropathology caused by deficiency of the housekeeping purine salvage function hypoxanthine guanine phospho- ribosyltransferase (HPRT) in the Lesch Nyhan Disease (LND), we have used microarray-based methods of global gene expression together with quantitative PCR and Western blot analysis to identify dysregulation of genes and aberrant cellular processes in human fibroblasts and in SH-SY5Y neuroblastoma cells made HPRT-deficient by transduction with a retrovirus stably expressing an shRNA targeted against HPRT. Analysis of the microarray expression data by Gene ontology (GO) and Gene Set Enrichment Analysis (GSEA) as well as by GeneSpring GX10 and Panther Classification System reveal that HPRT deficiency is accompanied by aberrations in a variety of pathways known to regulate neurogenesis or to be implicated in neurodegenerative disease, including the canonical Wnt/ß-catenin and the Alzheimer’s disease/presenilin signaling pathways. Dysregulation of the Wnt/ß-catenin pathway is confirmed by Western blot demonstration of cytosolic sequestration of ß-catenin during in vitro differentiation of the SH-SY5Y cells toward the neuronal phenotype. We also demonstrate that two key transcription factor genes known to be regulated by Wnt signaling and to be vital for the generation and function of dopaminergic neurons; i.e., Lmx1a and Engrailed 1, are down-regulated in the HPRT knockdown SH-SY5Y cells. In addition to the Wnt signaling aberration, we found that expression of presenilin-1 shows a severely disturbed expression in HPRT-deficient cells, reflected by marked instability of the 23kDa C-terminal fragment of presenilin-1 in knockdown cells. Western blot analysis of primary cultures of two LND patients with 2.5% and 0% residual HPRT activity also shows dysregulated b-catenin and presenilin-1 expression, including elevated levels of cytosolic phospho-catenin and, in one of the two patient cells, failure of nuclear transport. Similarly, the presenilin-1 processing defect was most clearly demonstrated by markedly increased levels of both the N-terminal and C-terminal presenilin-1 fragments in the human cell line with no detectable residual enzyme activity but less marked over-expression in the cell with 2.5% residual enzyme activity. These demonstrations of dysregulated Wnt and presenilin-1 signaling and impaired expression of transcription factors necessary for dopaminergic development reveal broad pleitropic neuro-regulatory defects played by HPRT and suggest new directions for investigating mechanisms of aberrant neurogenesis and neuropathology in LND and potential new targets for restoration of effective signaling in this neuro-developmental defect.
GSE24427 ImmunoHuman 2015Q2 250 8 The purpose of this study was to characterize the transcriptional effects induced by subcutaneous IFN-beta-1b treatment (Betaferon, 250 µg every other day) in patients with relapsing-remitting form of multiple sclerosis (MS).\r\nBy using Affymetrix DNA microarrays, we obtained genome-wide expression profiles of peripheral blood mononuclear cells from 25 MS patients within the first two years of IFN-beta administration.
GSE24533 ImmunoHuman Influenza 9 2 Pandemic influenza H1N1 (pdmH1N1) virus causes mild disease in humans but occasionally leads to severe complications and even death, especially in those who are pregnant or have underlying disease. Cytokine responses induced by pdmH1N1 viruses in vitro are comparable to other seasonal influenza viruses, suggesting the cytokine dysregulation as seen in H5N1 infection is not a feature of the pdmH1N1 virus. However, a comprehensive gene expression profile of pdmH1N1 in relevant primary human cells in vitro has not been reported. Type I alveolar epithelial cells are a key target cell in pdmH1N1 pneumonia. We carried out a comprehensive gene expression profiling using the Affymetrix microarray platform to compare the transcriptomes of primary human alveolar type I-like alveolar epithelial cells infected with pdmH1N1 or seasonal H1N1 virus.
GSE2461 ImmunoHuman IBD 8 1 IBS: Patients who have undergone a diagnostic program for gastrointestinal symptoms and where the diagnosis irritable bowel syndrome was reached.\r\nUC: Patients with well-diagnosed ulcerative colitis
GSE24695 ImmunoHuman Influenza 4 1 Transcriptional response to virus infection in mice lacking type I and type III signaling\r\nThe transcriptional response to virus infection is thought to be predominantly induced by interferon (IFN) signaling. Here we demonstrate that, in the absence of IFN signaling, an IFN-like transcriptome is still maintained. This transcriptional activity is mediated from IFN-stimulated response elements (ISREs) that bind to both the IFN stimulated gene factor 3 (ISGF3) as well as to IFN response factor 7 (IRF7). Through a combination of both in vitro biochemistry and in vivo transcriptional profiling, we have dissected what constitutes IRF-specific, ISGF3-specific, or universal ISREs. Taken together, the data presented here suggests that IRF7 can induce an IFN-like transcriptome in the absence of type-I or -III signaling and therefore provides a level of redundancy to cells to ensure the induction of the antiviral state.
GSE24706 ImmunoHuman SLE 48 1 Total 48 samples with different ANA titer were analyzed for their gene expression profiles with Illumina HumanWG-6 V3 chips
GSE24742 ImmunoHuman Arthritis 24 3 Objective: Rituximab displays therapeutic benefits in the treatment of rheumatoid arthritis (RA) patients resistant to TNF blockade. However, the precise role of B cells in the pathogenesis of RA is still unknown. In this study we investigated the global molecular effects of rituximab in synovial biopsies obtained from anti-TNF resistant RA patients before and after administration of the drug.\r\nMethods: Paired synovial biopsies were obtained from the affected knee of anti-TNF resistant RA patients before (T0) and 12 weeks after initiation of rituximab therapy (T12). Total RNA was extracted, labeled according to standard Affymetrix procedures and hybridized on GeneChip HGU133 Plus 2.0 slides. Immunohistochemistry and quantitative real-time PCR experiments were performed to confirm the differential expression of selected transcripts.\r\nResults: According to paired Student’s t-tests, 549 out of 54,675 investigated probe sets were differentially expressed between T0 and T12. Pathway analysis revealed that genes down-regulated between T0 and T12 were significantly enriched in immunoglobulin genes, and genes involved in chemotaxis, leucocyte activation and immune responses (Gene Ontology annotations). By contrast, genes up-regulated between T0 and T12 were significantly enriched in transcripts involved in cell development (Gene Ontology annotation) and wound healing (GSEA). At baseline, higher synovial expression of immunoglobulin genes was associated with response to therapy.\r\nConclusion: Rituximab displays unique effects on global gene expression profiles in synovial tissue of RA patients. These observations open new perspectives in the understanding of the biological effects of the drug and in the selection of patients likely to benefit from this therapy.
GSE24745 ImmunoHuman Asthma 30 3 Background: Allergen inhalation challenge in mild asthmatics induces airflow obstruction, airway hyperresponsiveness and inflammation, providing a model for hypothesis-generating experiments to understand regulation of these responses. We have sought to evaluate the peripheral whole blood transcriptome, post-challenge compared to pre-challenge, and to determine the effect of globin mRNA reduction methodology. Methods: Asthmatic subjects (20-60 years of age, with stable, mild allergic asthma, n=17) underwent allergen inhalation challenges. All subjects had an early asthmatic response of = 20% fall in FEV1; most had a late phase response of = 15% fall in FEV1. Blood was collected immediately prior to, and two hours after allergen challenge. Transcriptome analysis was performed using Affymetrix GeneChip® Human Gene 1.0 ST arrays, with and without globin mRNA reduction (PAX-GR and PAX-NGR, respectively) in 4 subjects. Replication studies for expression of nine genes contributing to the top canonical pathway, Nrf2-mediated oxidative stress response pathway, were performed with 5 independent subjects with microarray data, also with the same 4 subjects had microarray results and 8 other independent subjects with QPCR. Data were analyzed using paired t-test and Partek® Genomics Suite™.\r\nResults: The number of differentially expressed probe sets from PAX-NGR samples was twice that of PAX-GR samples. Paired analysis of each subjects' pre- and post-sample additionally demonstrated twice the power to detect differentially expressed probe sets. The Nrf2-mediated oxidative stress response pathway was identified as the top canonical pathway in the PAX-NGR samples. ATP-binding cassette sub-family C member 1 (ABCC1) gene was significantly reduced two hours after allergen challenge in the 5 subjects’ microarray dataset and the 2 QPCR replication datasets with P < 0.05. Conclusions: Globin mRNA reduction does not provide benefits to detect differentially expressed genes during allergen inhalation challenge. Allergen inhalation challenge is associated with decreased peripheral blood cell transcript level of ABCC1 gene.
GSE24767 ImmunoHuman Psoriasis 22 3 We sought to provide a comprehensive evaluation of the effects of TNF-a and IL-17 on the keratinocyte gene profile in order to identify genes that might be co-regulated by these cytokines. We then sought to determine how genes that were synergistically activated by both cytokines relate to the psoriasis transcriptome. Here, we identified 160 unique genes that were synergistically up-regulated by IL-17 and TNF-a and 188 unique genes where the two cytokines had at least an additive effect. Among highly up-regulated genes were those involved in neutrophil and lymphocyte chemotaxis, inflammation, and epidermal differentiation. Synergistically up-regulated genes included some of the highest expressed genes in lesional psoriatic skin with an impressive correlation between IL-17/TNF-a induced genes and the psoriasis gene signature. In conclusion, keratinocytes may be key drivers of pathogenetic inflammatory circuits in psoriasis through integrating responses to TNF-a and IL-17. This may explain high efficacy of targeting psoriasis with either anti-TNF-a or agents that block Th17 T-cells/IL-17 and has important implications for the development of new therapeutic agents.
GSE25101 ImmunoHuman Arthritis 32 1 Introduction: A number of genetic-association studies have identified genes contributing to AS susceptibility but such approaches provide little information as to the gene activity changes occurring during the disease process. Transcriptional profiling generates a “snapshot” of the sampled cells activity and thus can provide insights into the molecular processes driving the disease process. We undertook a whole-genome microarray approach to identify candidate genes associated with AS and validated these gene-expression changes in a larger sample cohort. Methods: 18 active AS patients, classified according to the New York criteria. and 18 gender-and age-matched controls were profiled using Illumina HT-12 Whole-Genome Expression BeadChips which carry cDNAs for 48000 genes and transcripts. Class comparison analysis identified a number of differentially expressed candidate genes. These candidate genes were then validated in a larger cohort using qPCR-based TaqMan Low Density Arrays (TLDAs). Results: 239 probes corresponding to 221 genes were identified as being significantly different between patients and controls with a p-value <0.0005 (80% confidence level of false discovery rate). Forty seven genes were then selected for validation studies, using the TLDAs. Thirteen of these genes were validated in the second patient cohort with 12 down-regulated 1.3-2-fold and only 1 upregulated (1.6-fold). Among a number of identified genes with well-documented inflammatory roles we also validated genes that might be of great interest to the understanding of AS progression such as SPOCK2 (osteonectin) and EP300 which modulate cartilage and bone metabolism. Conclusion: We have validated a gene expression signature for AS from whole blood and identified strong candidate genes that may play roles in both the inflammatory and joint destruction aspects of the disease.
GSE25160 ImmunoHuman Arthritis 26 1 We used microarrays to identify markers predicting responder status in tocilizumab treatment in rheumatoid arthritis in 13 patients at week 0 and week 4 of treatment.
GSE25220 ImmunoHuman IBD 44 3 Study 1: Transcriptomic profiles in colon tissue from inflammatory bowel diseases patients in relation to N-nitroso compound exposure and colorectal cancer risk\r\nStudy 1: N-nitroso compounds (NOC) have been suggested to play a role in human cancer development but definitive evidence is still lacking. In this study we investigated gene expression modifications induced in human colon tissue in relation to NOC exposure to gain insight in the relevance of these compounds in human colorectal cancer (CRC) development. Since there are indications that inflammation stimulates endogenous NOC formation, the study population consisted of patients with inflammatory bowel disease (IBD) and irritable bowel syndrome patients as controls without inflammation. Strong transcriptomic differences were identified in colonic biopsies from IBD patients and compared to controls that enhance the understanding of IBD pathophysiology. However, fecal NOC levels were not increased in IBD patients, suggesting that inflammation did not stimulate NOC formation. By relating gene expression changes of all subjects to fecal NOC levels, we did, however, identify a NOC exposure-associated transcriptomic response that suggests that physiological NOC concentrations may induce genotoxic responses and chromatin modifications in human colon tissue, both of which are linked to carcinogenicity. In a network analysis, chromatin modifications were linked to 11 significantly modulated histone genes, pointing towards a possible epigenetic mechanism that may be relevant in comprehending the molecular basis of NOC-induced carcinogenesis. We conclude that NOC exposure is associated with gene expression modifications in the colon that may increase CRC risk in humans.\r\nStudy 2: Red meat intake-induced increases in fecal water genotoxicity correlate with pro-carcinogenic gene expression changes in the human colon\r\nStudy 2: Red meat consumption is associated with an increased colorectal cancer (CRC) risk, which may be due to an increased endogenous formation of genotoxic N-nitroso compounds (NOCs). To assess the impact of red meat intake on potential risk factors of CRC, we investigated the effect of a 7-day dietary red meat intervention in human subjects on endogenous NOC formation and fecal water genotoxicity in relation to transcriptomic changes induced in colonic tissue. In order to evaluate the potential effect of an inflamed colon on endogenous nitrosation, the study population consisted of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) control subjects without inflammation. The intervention had no effect on fecal NOC formation but fecal water genotoxicity significantly increased in response to red meat intake. Since IBD patients showed no difference in fecal NOC formation or fecal water genotoxicity levels as compared to IBS controls, for transcriptomic analyses, all subjects were grouped together. Genes significantly correlating with the increase in fecal water genotoxicity were involved in biological pathways indicative of genotoxic effects, including modifications in DNA damage, cell cycle, and apoptosis pathways. Moreover, WNT signaling and nucleosome remodeling pathways were modulated that are known to play a part in the carcinogenic process in the human colon. These results are in line with a possible oxidative effect of dietary heme. We conclude that the gene expression changes identified in this study corroborate the genotoxic potential of diets high in red meat and point towards a possible risk of CRC development in humans.
GSE25400 ImmunoHuman Psoriasis 16 5 Analysis of stratified epidermal cultures treated with IL-1a, IL-1F5, IL-1F6, IL-1F8 and IL-1F9 to determine the effects of these cytokines at 24h. Results provide insight into the role of IL-1 family cytokines in the pathogenesis of psoriasis.
GSE26104 ImmunoHuman 2015Q2 32 6 We aimed to identify specific biomarkers of IFN-beta bioactivity in order to compare their gene expression induction by type I IFNs with the MxA, and to investigate their potential role in MS pathogenesis. Gene expression microarrays were performed in PBMC from MS patients who developed neutralizing antibodies (NAB) to IFN-beta. Nine genes followed patterns in gene expression over time similar to the MX1 and were selected for further experiments: IFI6, IFI27, IFI44L, IFIT1, HERC5, LY6E, RSAD2, SIGLEC1, and USP18. In vitro experiments revealed specific induction of selected biomarkers by IFN-beta but not IFN-gamma, and several markers, in particular USP18 and HERC5, were significantly induced at lower IFN-beta concentrations and more selective than the MX1 as biomarkers of IFN-beta bioactivity. In addition, USP18 expression was deficient in MS patients compared with healthy controls (p=0.0004). We propose specific biomarkers that may be considered in addition to the MxA to evaluate IFN-beta bioactivity, and to further explore their implication in MS pathogenesis.
GSE26112 ImmunoHuman Arthritis 34 1 Gene expression profiles were obtained from 17 children with rheumatoid factor negative (RF-) polyarticular juvenile idiopathic arthritis (JIA). The disease was inactive in all patients at visit 1. Thee disease remained inactive at visit 2 for 9 patients, while the other 8 patients were experiencing a disease flare at visit 2. The goal of the study was to better understand the underlying molecular biology of flares in JIA\r\nTotal RNA was obtained from PBMC at two different times in the course of disease
GSE26276 ImmunoHuman ALS 9 2 We compared gene expression profiles of ALS patients with normal patients and with multifocal motor neuropathy (MMN) patients.
GSE26296 ImmunoHuman COPD 6 1 Lung myeloid dendritic cells isolated from emphysema but not healthy subjects induce Th1 and Th17 cells differentiation. The goal of this study is to identify the genes differentially expressed by lung myeloid dendritic cells from healthy or emphysema subjects. These genes may play crucial roles in directing Th1 and Th17 cells differentiation.
GSE26438 ImmunoHuman NormalControl 12 2 Talactoferrin alfa (TLF) is a unique recombinant version of human lactoferrin, an important immunomodulatory protein present in exocrine secretions and in the secondary granules of neutrophils. Talactoferrin has demonstrated anti-cancer activity in preclinical studies and in Phase III clinical trials in patients with Renal Cell Cancer and non-small cell lung cancer. We have shown that TLF induces the maturation of human DCs derived from monocytes, suggesting that the linkage of the innate and adaptive immunity through DC maturation is a key immune function mediated by TLF. In this study we used genome-wide expression analysis to explore the mechanisms by which TLF leads to the functional maturation of DC. We show that GMP level recombinant TLF activates human DCs in a Toll-like receptor (TLR) -2 and -4 dependent manner.
GSE26554 ImmunoHuman Arthritis 91 5 Juvenile idiopathic arthritis (JIA) is the most common chronic childhood rheumatic disease in the Western world. To identify novel JIA predisposing loci, a genome-wide association study (GWAS) in 814 Caucasian JIA cases and 3058 Caucasian controls was completed. After adjusting for the most significant HLA associations, the strongest novel associations included rs6479891 (10q21, odds ratio (OR)=1.59, P=1.3x10-8) and rs10761747 (OR=1.34, P=4.0x10-5) within JMJD1C; rs12719740 (15q26, OR=1.47, P=3.3x10-7) near FAM169B; rs4688011 (3q13, OR=1.33, P=1.1x10-4) within C3orf1 and rs4254850 (4q31, OR=0.85, P=7.8x10-3) near IL15. Eleven SNPs were genotyped in Caucasian replication cohorts (1744 cases, 7010 controls) and meta-analysis continued to provide evidence for association with three of the SNPs (rs6479891, P=4.3x10-5; rs12719740, P=5.2x10-4; rs4688011, P=3.6x10-7). Analysis of expression data from 68 JIA cases and 23 controls overlapping in the GWAS cohort1 and published lymphoblastoid cell lines (LCL)2 showed cis eQTL associations for JMJD1C SNPs (P=0.01 and P=1.6x10-6, respectively), and the C3orf1 SNP (P=5.7x10-6).
GSE26594 ImmunoHuman PulmonaryFibrosis 6 0 Idiopathic pulmonary fibrosis (IPF) is associated with the accumulation of collagen-secreting fibroblasts and myofibroblasts in the lung parenchyma. Many mechanisms contribute to their accumulation, including resistance to apoptosis. In previous work, we showed that exposure to the pro-inflammatory cytokines, TNF-a and IFN-? reverses fibroblast resistance to apoptosis. The goal of this study was to investigate the underlying mechanism. Based on an initial interrogation of the transcriptomes of unstimulated and TNF-a and IFN-?-stimulated primary lung fibroblasts and the lung fibroblast cell line, MRC5, we show here that among Fas-signaling pathway molecules, Fas expression was increased ~6-fold in an NF-?B and p38mapk-dependent fashion. Prevention of the increase in Fas expression using Fas siRNAs blocked the ability of TNF-a and IFN-? to sensitize fibroblasts to Fas ligation induced-apoptosis; while enforced adenovirus-mediated Fas overexpression was sufficient to overcome basal resistance to Fas-induced apoptosis. Examination of lung tissues from IPF patients revealed low to absent staining of Fas in fibroblastic cells of fibroblast foci. Collectively, these findings suggest that increased expression of Fas is necessary and sufficient to overcome the resistance of lung fibroblasts to Fas-induced apoptosis. They also suggest that approaches aimed at increasing Fas expression by lung fibroblasts and myofibroblasts may be therapeutically relevant.
GSE26866 ImmunoHuman Psoriasis 37 1 In this study, we sought to establish the usefulness of LCM on cDNA microarray analysis. We reported that LCM samples improved the sensitivity of detection of differentially expressed genes over conventional bulk tissue analysis. We also provided the new information of chemokine and its receptor interaction within psoriatic lesional skin.
GSE26927 ImmunoHuman 2015Q2 118 6 Neurodegenerative diseases of the central nervous system are characterised by pathogenetic cellular and molecular changes in specific areas of the brain that lead to the dysfunction and/or loss of explicit neuronal populations. Despite exhibiting different clinical profiles and selective neuronal loss, common features such as abnormal protein deposition, dysfunctional cellular transport, mitochondrial deficits, glutamate excitotoxicity and inflammation are observed in most, if not all, neurodegenerative disorders, suggesting converging pathways of neurodegeneration. We have generated comparative genome-wide gene expression data for Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, multiple sclerosis, Parkinson’s disease and schizophrenia using an extensive cohort of well characterised post-mortem CNS tissues. The analysis of whole genome expression patterns across these major disorders offers an outstanding opportunity not only to look into exclusive disease specific changes, but more importantly to uncover potential common molecular pathogenic mechanisms that could be targeted for therapeutic gain. Surprisingly, no dysregulated gene that passed our selection criteria was found in common across all 6 diseases using our primary method of analysis. However, 61 dysregulated genes were shared when comparing five and four diseases. Our analysis indicates firstly the involvement of common neuronal homeostatic, survival and synaptic plasticity pathways. Secondly, we report changes to immunoregulatory and immunomodulatory pathways in all diseases. Our secondary method of analysis confirmed significant up-regulation of a number of genes in diseases presenting degeneration and showed that somatostatin was downregulated in all 6 diseases. The latter is supportive of a general role for neuroinflammation in the pathogenesis and/or response to neurodegeneration. Unravelling the detailed nature of the molecular changes regulating inflammation in the CNS is key to the development of novel therapeutic approaches for these chronic conditions.
GSE26949 ImmunoHuman SLE 12 1 Systemic lupus erythematosus (SLE) is characterized by increased vascular risk due to premature atherosclerosis independent of traditional risk factors. We previously proposed that interferon-a plays a crucial role in premature vascular damage in SLE. IFN-a alters the balance between endothelial cell apoptosis and vascular repair mediated by endothelial progenitor cells (EPCs) and myeloid circulating angiogenic cells (CACs). Here we demonstrate that IFN-a promotes an antiangiogenic signature in SLE and control EPCs/CACs, characterized by transcriptional repression of IL-1a and ß, IL-1 receptor 1 and vascular endothelial growth factor A (VEGF-A) and upregulation of IL-1 receptor antagonist (IL-1RN) and the decoy receptor IL1-R2. IL-1ß promotes significant improvement in the functional capacity of lupus EPCs/CACs, therefore abrogating the deleterious effects of IFN-a.\r\nWe used microarrays to analyze the effect of IFNa on peripheral blood EPCs/CACs and on bone marrow EPCs exposed to proangiogenic stimulation.
GSE26950 ImmunoHuman SLE 12 1 Systemic lupus erythematosus (SLE) is characterized by increased vascular risk due to premature atherosclerosis independent of traditional risk factors. We previously proposed that interferon-a plays a crucial role in premature vascular damage in SLE. IFN-a alters the balance between endothelial cell apoptosis and vascular repair mediated by endothelial progenitor cells (EPCs) and myeloid circulating angiogenic cells (CACs). Here we demonstrate that IFN-a promotes an antiangiogenic signature in SLE and control EPCs/CACs, characterized by transcriptional repression of IL-1a and ß, IL-1 receptor 1 and vascular endothelial growth factor A (VEGF-A) and upregulation of IL-1 receptor antagonist (IL-1RN) and the decoy receptor IL1-R2. IL-1ß promotes significant improvement in the functional capacity of lupus EPCs/CACs, therefore abrogating the deleterious effects of IFN-a.\r\nWe used microarrays to analyze the effect of IFNa on peripheral blood EPCs/CACs and on bone marrow EPCs exposed to proangiogenic stimulation.
GSE26951 ImmunoHuman SLE 10 1 Systemic lupus erythematosus (SLE) is characterized by increased vascular risk due to premature atherosclerosis independent of traditional risk factors. We previously proposed that interferon-a plays a crucial role in premature vascular damage in SLE. IFN-a alters the balance between endothelial cell apoptosis and vascular repair mediated by endothelial progenitor cells (EPCs) and myeloid circulating angiogenic cells (CACs). Here we demonstrate that IFN-a promotes an antiangiogenic signature in SLE and control EPCs/CACs, characterized by transcriptional repression of IL-1a and ß, IL-1 receptor 1 and vascular endothelial growth factor A (VEGF-A) and upregulation of IL-1 receptor antagonist (IL-1RN) and the decoy receptor IL1-R2. IL-1ß promotes significant improvement in the functional capacity of lupus EPCs/CACs, therefore abrogating the deleterious effects of IFN-a.\r\nWe used microarrays to analyze the effect of IFNa on peripheral blood EPCs/CACs and on bone marrow EPCs exposed to proangiogenic stimulation.
GSE26952 ImmunoHuman Psoriasis 16 2 The expression and function of tight junction genes, in particular claudin-1, was studied in order to further understanding of the biology underlying atopic dermatitis.
GSE26975 ImmunoHuman SLE 29 2 Our group has proposed that low-density granulocytes (LDGs) play an important role in lupus pathogenesis, as they can damage endothelial cells and synthesize increased levels of proinflammatory cytokines and type I interferons. LDGs have a heightened capacity to synthesize neutrophil extracellular traps (NETs). NETs from LDGs display increased levels of bactericidal and immunostimulatory proteins, such as the cathelicidin LL37 and externalize double-stranded DNA (dsDNA). Lupus netting LDGs have increased capacity to kill endothelial cells and expose IL-17. Through NETosis, lupus neutrophils stimulate plasmacytoid DCs to synthesize IFN-a. Our results further expand the potential pathogenic role of aberrant lupus neutrophils through a NET-mediated effect.\r\nWe used microarrays to analyze the gene expression of neutrophils in healthy and lupus patients, and of low-density granulocytes in lupus patients.
GSE27002 ImmunoHuman COPD 23 2 Cigarette smoking is the leading cause of emphysema in the United States. Alveolar macrophages play a critical role in the inflammation-mediated remodeling of the lung parenchyma in emphysema. However, the exact gene pathways and the role of DNA methylation in moderating this pathological transformation are not known. In order to more exactly understand this process, we compared genome-wide expression and methylation signatures of alveolar macrophages isolated from heavy smokers with those isolated from non-smoking controls. We found enrichment of differential methylation in genes from immune system and inflammatory pathways as determined by standard pathway analysis. Consistent with recent findings, significant methylation changes were particularly enriched in the areas flanking CpG islands (CpG shores). Analysis of matching gene expression data demonstrated a parallel enrichment for changes in immune system and inflammatory pathways. We conclude that alveolar macrophages from the lungs of smokers demonstrate coordinated changes in DNA methylation and gene expression that link to inflammation pathways. We suggest that further studies of DNA methylation in immune and inflammation-related gene expression are needed to understand the pathogenesis of emphysema and other smoking-related diseases.
GSE27011 ImmunoHuman Asthma 54 2 Background: Around 5% of children with asthma suffer from chronic symptoms and/or severe exacerbations despite extensive treatment. The causes of severe therapy-resistant childhood asthma are poorly understood. Objectives: To define global patterns of gene expression in severe therapy-resistant vs. controlled asthma and healthy controls. Methods: Children with severe, therapy-resistant (SA, n=20) and controlled asthma (CA, n=20) were identified from a Swedish nation-wide study including extensive clinical and immunological characterisation. In addition, healthy controls were recruited (Ctrl, n=19). White blood cells were isolated and the global transcriptome profile was characterised using the Affymetrix Human Gene ST 1.0 chip. Results: 1378 genes were differentially expressed in one or several of the CA vs. Ctrl, SA vs. CA or SA vs. Ctrl contrasts. A large number could uniquely differentiate the SA group from the CA (n=351 genes) and Ctrl (n=315) groups, whereas fewer genes differentiated the CA from the Ctrl group (n=149). Several non-coding RNAs were found up-regulated in SA compared to CA or Ctrl. Three significantly enriched KEGG pathways were represented; bitter taste transduction, TAS2Rs (up-regulated mostly in SA), natural killer cell mediated cytotoxicity (up-regulated in CA) and N-Glycan biosynthesis (down-regulated in SA). An unsupervised hierarchical clustering of the 1378 genes could crudely separate the SA, CA and Ctrl individuals. Conclusion: Our data indicate a separation in gene expression patterns between children with severe, therapy-resistant asthma and controlled persistent asthma, and suggest novel pathways characterizing the severe therapy-resistant asthma phenotype.
GSE27131 ImmunoHuman Influenza 21 2 Using PAXgene tubes, peripheral blood samples were collected from seven patients >18 years with documented pdm(H1N1) influenza, bilateral chest infiltrates, and in need of ventilation support. Significant co-morbidity was exclusion criterion. Expression profiles were compared with 7 age matched controls. Using a false discovery rate < 5% and an absolute fold change > 2, 370 genes were differentially expressed in case and controls.\r\nA second sample was collected after ca 6 days in the 7 patients and temporal changes in expression profiles investigated. Over expressed putative mediators of inflammatory lung dammage were measured on the protein level.
GSE2737 ImmunoHuman Psoriasis 11 1 Gene expression profiling was performed on biopsies of affected and unaffected psoriatic skin and normal skin from seven Japanese patients to obtain insights into the pathways that control this disease. U95A Affymetrix DNA chips that contain oligonucleotide arrays of approximately 12,000 well-characterized human genes were used in the study. The statistical analysis of the Affymetrix data, based on the ranking of the Student-test statistic, revealed a complex regulation of molecular stress and immune gene responses. The majority of the 266 induced-genes in affected and unaffected psoriatic skin were involved with interferon mediation, immunity, cell-adhesion, cytoskeleton restructuring, protein trafficking and degradation, RNA regulation and degradation, signaling transduction, apoptosis and atypical epidermal cellular proliferation and differentiation. The disturbances in the normal protein degradation equilibrium of skin were reflected by the significant increase in the gene expression of various protease inhibitors and proteinases including the induced components of the ATP/ubiquitin-dependent non-lysosomal proteolytic pathway that is involved with peptide processing and presentation to T-cells. Some of the upregulated genes, such as TGM1, IVL, CSTA, FABP5 and SPRR, are well known psoriatic markers involved in atypical epidermal cellular organization and differentiation. In the comparison between the affected and unaffected psoriatic skin, the transcription factor JUNB was found at the top of the statistical rankings for the 51 significantly upregulated genes in affected skin, suggesting that it has an important but as yet undefined role in psoriasis. Our gene expression data and analysis suggest that psoriasis is a chronic IFN and T-cell-mediated immune disease of the skin where the imbalance in epidermal cellular structure, growth and differentiation arises from the molecular antiviral stress signals initiating inappropriate immune responses.
GSE27390 ImmunoHuman Arthritis 19 1 Gene expression profiling of BMMC from patients with rheumatoid arthritis (RA) vs. osteoarthritis (OA).
GSE27427 ImmunoHuman SLE 47 4 Mature neutrophis were freshly isolated from blood of pediatric systemic lupus erythematosus (SLE) patients and healthy donors. Illumina microarray was used to assess transcriptional changes between SLE group and Control group. To uderstand further the gene expression difference between SLE and healthy neutrofils, neutrophils from healthy donors were cultured with autologous sera, SLE sera or Interferon and microarray data was used to compare with fresh SLE neutrophils.
GSE27536 ImmunoHuman COPD 54 5 Study the training exercise effects in chronic obstructive pulmonary disease (COPD) patients and aged-matched healthy individuals. Skeletal muscle biopsies from 9 stable COPD patients with normal fat free mass index (FFMI, 21Kg/m2) (COPDN), 6 COPD patients with low FFMI (16Kg/m2) (COPL), and 12 healthy sedentary subjects (FFMI 21Kg/m2) before and after 8 weeks of a supervised endurance exercise program were analyzed.
GSE27543 ImmunoHuman 2015Q2 16 4 Study the effects of 3 weeks training exercise in chronic obstructive pulmonary disease (COPD) patients and healthy individuals. Skeletal muscle biopsies of 5 COPD patients (aged 63±2 year) and 3 age-matched healthy individuals were studied before and after 3 weeks of a supervised endurance training program.
GSE27597 ImmunoHuman COPD 72 3 BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease consisting of emphysema, small airway obstruction, and/or chronic bronchitis that results in significant loss of lung function over time. METHODS: In order to gain insights into the molecular pathways underlying progression of emphysema and explore computational strategies for identifying COPD therapeutics, we profiled gene expression in lung tissue samples obtained from regions within the same lung with varying amounts of emphysematous destruction from smokers with COPD (8 regions x 8 lungs = 64 samples). Regional emphysema severity was quantified in each tissue sample using the mean linear intercept (Lm) between alveolar walls from micro-CT scans. RESULTS: We identified 127 genes whose expression levels were significantly associated with regional emphysema severity while controlling for gene expression differences between individuals. Genes increasing in expression with increasing emphysematous destruction included those involved in inflammation, such as the B-cell receptor signaling pathway, while genes decreasing in expression were enriched in tissue repair processes, including the transforming growth factor beta (TGF beta) pathway, actin organization, and integrin signaling. We found concordant differential expression of these emphysema severity-associated genes in four cross-sectional studies of COPD. Using the Connectivity Map, we identified GHK as a compound that can reverse the gene-expression signature associated with emphysematous destruction and induce expression patterns consistent with TGF beta pathway activation. Treatment of human fibroblasts with GHK recapitulated TGF beta-induced gene-expression patterns, led to the organization of the actin cytoskeleton, and elevated the expression of integrin beta1. Furthermore, addition of GHK or TGF beta restored collagen I contraction and remodeling by fibroblasts derived from COPD lungs compared to fibroblasts from former smokers without COPD. CONCLUSIONS: These results demonstrate that gene-expression changes associated with regional emphysema severity within an individual¿s lung can provide insights into emphysema pathogenesis and identify novel therapeutic opportunities for this deadly disease. They also suggest the need for additional studies to examine the mechanisms by which TGF beta and GHK each reverse the gene-expression signature of emphysematous destruction and the effects of this reversal on disease progression.
GSE27688 ImmunoHuman 2015Q2 30 2 Intense immunosuppression followed by autologous hematopoietic stem cell transplantation (aHSCT) is a potential treatment for patients suffering from aggressive multiple sclerosis (MS). However it remains unresolved whether autologous CD34+ hematopoietic progenitor cells of MS patients show gene expression differences prior to aHSCT that indicate a preset proinflammatory state, which would then also predispose to or predetermine recurrence of the autoimmune disease. To approach this key point we compared the gene expression signature of CD34+ and CD34- cells collected from MS patients and healthy donors (HD). Whole genome gene expression of CD34+ and CD34- cells was analysed with the Human 4x44K Design Array (Agilent-Technologies). As main observation we found only minor differences in the gene expression signature of MS patients compared to HD. Only a single gene, troponin-type-1 (TNNT1), reached statistical significance after correction for multiple comparisons (logFC=3.1, p<0.01). There was a decreased expression of several protease genes, myeloperoxidase (MPO), neutrophil-elastase (ELA2), cathepsin-G (CTSG) and serine-protease 21 (PRSS21) in HPCs of MS patients, albeit not reaching statistical significance. In summary we did not detect substantial alterations in the gene expression profile of CD34+ HPCs in MS. Our data support the use of autologous hematopoietic stem cell transplantation for treatment of an autoimmune disease.
GSE27702 ImmunoHuman Influenza 12 3 Macrophages were infected with low (PR8) and high pathogenic influenza viruses (FPV and H5N1). To our surprise a genome-wide comparative systems biology approach revealed that in contrast PR8 infections with HPAIV H5N1 and FPV result in a reduced immune response of human macrophages contradicting a primary role of this cell type for the cytokine storm.\r\nOur data point to a viral strategy of HPAIV to bypass a major amplifier of the initial local inflammatory response thereby hampering antiviral effector mechanisms and facilitating virus spreading and systemic disease.
GSE2779 ImmunoHuman Arthritis 28 4 Early, low risk IPSS (International Prognostic Scoring System) myelodysplasia (MDS) is a heterogeneous disorder where the molecular and cellular haematopoietic defects are poorly understood. To gain insight into this condition, we analyzed gene expression profiles of marrow CD34+ progenitor cells from normal karyotype, low blast count MDS patients, age-matched controls and patients with non-MDS anaemia. The aim of the study was to further understanding of the cellular defect in MDS and to identify biomarkers of disease
GSE27876 ImmunoHuman Asthma 19 3 To further development of our gene expression approach to biodosimetry, we have employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to distinguish asthma and normal subjects. We analyzed gene expression patterns of the peripheral blood cells from asthma patients compared with those from normal subjects using microarray analyses. In addition, we analyzed gene expression patterns of the LPS or HDM-treated THP1 cells compared with those from non-treated THP1 cells. And we analyzed the microarray data through clustering analysis, signaling pathway analysis and others.
GSE27887 ImmunoHuman Psoriasis 35 4 Background: Atopic dermatitis (AD) is a common inflammatory skin disease exhibiting a predominantly Th2/“T22” immune activation and a defective epidermal barrier. Narrow-band UVB (NB-UVB) is considered an efficient treatment for moderate to severe AD. In psoriasis, NB-UVB has been found to suppress the Th1/Th17 immune polarization with subsequent reversal of epidermal hyperplasia. The immunomodulatory effects of this treatment are largely unknown in AD. Our study evaluates the effects of NB-UVB on immune and barrier abnormalities in AD, aiming to establish reversibility of disease and biomarkers of therapeutic response. Methods: 12 moderate-to-severe chronic AD patients received NB-UVB phototherapy 3 times weekly for up to 12 weeks. Lesional and non-lesional skin biopsies were obtained before and after treatment and evaluated by gene-expression and immunohistochemistry studies. Results: All patients had at least a 50% reduction in SCORing of AD (SCORAD) index with NB-UVB phototherapy. The Th2, T22, and Th1 immune pathways were suppressed and measures of epidermal hyperplasia and differentiation also normalized after phototherapy. The reversal of disease activity was associated with elimination of inflammatory leukocytes, Th2/“T22”-associated cytokines and chemokines, and normalized expression of barrier proteins. Conclusions: Our study shows reversal of both the epidermal defects and underlying immune activation in AD. By determining the correlation of variables with therapeutic response, we have defined a set of biomarkers of disease response that associate resolved Th2 and T22 inflammation with reversal of barrier pathology. This data supports the “inside-out” hypothesis of AD, suggesting that it is a disease primarily driven by an immune stimulus.
GSE28042 ImmunoHuman Sclerosis 94 2 Background: In this study we aimed to identify peripheral blood mononuclear cell (PBMC) gene expression profiles predictive of poor outcomes in idiopathic pulmonary fibrosis (IPF)\r\nMethods: Microarray analyses of PBMC were performed in 120 patients from discovery (n=45) and replication cohorts (n=75). Genes and pathways associated with transplant-free survival (TFS) were identified and confirmed by qRT-PCR.\r\nFindings: 52 genes were predictive of TFS in a discovery cohort (FDR<5%, Cox score above 2.5 or below -2.5). Clustering the replication cohort samples using these genes distinguished two patient groups with significantly different TFS (hazard ratio 1.96, 95%CI 1.01-3.8, P=0.018). Decreased expression of “The co-stimulatory signaling during T cell activation” Biocarta pathway and in particular CD28, ICOS, LCK and ITK was associated with shorter TFS times in each cohort (FDR<5%). qRT-PCR expression of CD28, ICOS, LCK and ITK correlated with the microarray results in the discovery cohort (P<0.05) and their decreased expression was predictive of shorter TFS in the replication cohort (P<0.05). A genomic and clinical model demonstrated an area under the ROC curve of 78.5% at 2.4 months for death and lung transplant prediction.\r\nInterpretation: Our results suggest that CD28, ICOS, LCK and ITK are outcome biomarkers in IPF.
GSE28146 ImmunoHuman AD 30 3 Alzheimer's disease (AD) is a devastating neurodegenerative disorder that threatens to reach epidemic proportions as our population ages. Although much research has examined molecular pathways associated with AD, relatively few studies have focused on critical early stages. Our prior microarray study correlated gene expression in human hippocampus with AD markers. Results suggested a new model of early-stage AD in which pathology spreads along myelinated axons, orchestrated by upregulated transcription and epigenetic factors related to growth and tumor suppression (Blalock et al., 2004). However, the microarray analyses were performed on RNA from fresh frozen hippocampal tissue blocks containing both gray and white matter, potentially obscuring region-specific changes. In the present study, we used laser capture microdissection to exclude major white matter tracts and selectively collect CA1 hippocampal gray matter from formalin-fixed, paraffin-embedded (FFPE) hippoc ampal sections of the same subjects assessed in our prior study. Microarray analyses of this gray matter-enriched tissue revealed many correlations similar to those seen in our prior study, particularly for neuron-related genes. Nonetheless, in the laser-captured tissue, we found a striking paucity of the AD-associated epigenetic and transcription factor genes that had been strongly overrepresented in the prior tissue block study. In addition, we identified novel pathway alterations that may have considerable mechanistic implications, including downregulation of genes stabilizing ryanodine receptor Ca2+ release and upregulation of vascular development genes. We conclude that FFPE tissue can be a reliable resource for microarray studies, that upregulation of growth-related epigenetic/ transcription factors with incipient AD is predominantly localized to white matter, further supporting our prior findings and model, and that alterations in vascular and ryanodine receptor-relat ed pathways in gray matter are closely associated with incipient AD.
GSE28166 ImmunoHuman 2015Q2 36 6 Over the last decade, more than half of humans infected with highly pathogenic avian influenza (HPAI) H5N1 viruses have died, and yet virus-induced host signaling has yet to be clearly elucidated. Airway epithelia are known to produce inflammatory mediators that contribute to HPAI H5N1-mediated pathogenicity, but a comprehensive analysis of the host response in this cell type is lacking. Here, we leveraged a systems biology method called weighted gene correlation network analysis (WGCNA) to identify and statistically validate signaling sub-networks that define the dynamic transcriptional response of human bronchial epithelial cells after infection with influenza A/Vietnam/1203/2004 (H5N1, VN1203). A detailed examination of two sub-networks involved in the immune response and keratin filament formation revealed potential novel mediators of HPAI H5N1 pathogenesis, and additional experiments validated upregulation of these transcripts in response to VN1203 infection in C57BL/6 mice. Using emergent network properties, we provide fresh insight into the host response to HPAI H5N1 virus infection, and identify novel avenues for perturbation studies and potential therapeutic intervention of fatal HPAI H5N1 disease.
GSE28490 ImmunoHuman nomodel 47 0 Blood consists of different cell populations with distinct functions and correspondingly, distinct gene expression profiles. In this study, global miRNA expression profiling was performed across a panel of nine human immune cell subsets (neutrophils, eosinophils, monocytes, B cells, NK cells, CD4 T cells, CD8 T cells, mDCs and pDCs) to identify cell-type specific miRNAs. mRNA expression profiling was performed on the same samples, to determine if miRNAs specific to certain cell types down-regulated expression levels of their target genes. Six cell-type specific miRNAs (miR-143; neutrophil specific, miR-125; T cells and neutrophil specific, miR-500; monocytes and pDC specific, miR-150; lymphoid cells specific, miR-652 and miR-223; both myeloid cells specific) were negatively correlated with expression of their predicted target genes. These results were further validated using an independent cohort where similar immune cell subsets were isolated and profiled for both miRNA and mRNA expression. miRNAs negatively correlated with target gene expression in both cohorts were identified as candidates for miRNA-mRNA regulatory pairs and were used to construct a cell-type specific regulatory network. miRNA-mRNA pairs formed two distinct clusters in the network corresponding to myeloid (nine miRNAs) and lymphoid lineages (two miRNAs). Several myeloid specific miRNAs targeted common genes including ABL2, EIF4A2, EPC1 and INO80D; these common targets were enriched for genes involved in the regulation of gene expression (p < 9.0E-7). Those miRNA might therefore have significant further effect on gene expression by repressing the expression of genes involved in transcriptional regulation. The miRNA and mRNA expression profiles reported in this study form a comprehensive transcriptome database of various human blood cells and serve as a valuable resource for elucidating the role of miRNA mediated regulation in the establishment of immune cell identity.
GSE28656 ImmunoHuman IBD 8 1 Nkx2-3 is associated with inflammatory bowel disease (IBD). Nkx2-3 is expressed in microvascular endothelial cells and the muscuularis mucosa of the gastrointestinal tract. Human intestinal microvascular cells (HIMEC) are actively involved in the pathogenesis of IBD and IBD-associated microvascular dysfunction. To understand the cellular function of Nkx2-3 and its potential role underlying IBD pathogenesis, we investigated the genes regulated by Nkx2-3 in HIMEC usin cDNA microarray.
GSE28726 ImmunoHuman NormalControl 28 3 Microarray analysis was performed to determine the transcriptional profiles of NKT, CD1d-aGC+ Va24-, and CD4 T cells.
GSE28785 ImmunoHuman Arthritis 12 4 The effect of SAA1 treatment on global gene expression in THP-1 macrophages was studied. The study determined the gene expression upon wild-type SAA1 treatment, variant SAA1 treatment (p.Gly72Asp) and in untreated THP-1 macrophages. SAA1 treatment of macrophages induces the expression of genes involved in inflammation, angiogenesis, phagocytosis and tissue remodeling which are important in the pathogenesis of chronic inflammatory diseases such as atherosclerosis and rheumatoid arthritis.
GSE29133 ImmunoHuman COPD 6 1 Alveolar epithelial type II (ATII) cells play a critical role in homeostasis and repair process of the lungs. In lung diseases such as chronic obstructive pulmonary disease (COPD), ATII cells are damaged and fall into apoptosis or senescence. Until to date, global gene expression of ATII cells in COPD lungs has not been analyzed. We isolated ATII cells from three non-COPD and three COPD patients using a FACS method. Then, we performed microarray analysis to compare gene expression profiles of ATII cells between non-COPD and COPD patients.
GSE29378 ImmunoHuman AD 63 2 Along with the two hallmark pathologies—intracellular neurofibrillary tangles (NFTs) and extracellular amyloid plaques—transcriptional studies suggest that Alzheimer's disease (AD) results from dysfunction of many cellular pathways including synaptic transmission, cytoskeletal dynamics, and apoptosis. While these studies consistently point to the same pathways involved in AD, there is no consensus on which genes in each pathway are disease-relevant, much less on whether these genes play causative roles or are downstream effects of disease progression. To address these issues, we have performed a large-scale transcriptional analysis in brain of individuals with advanced AD and non-demented controls, focusing specifically on CA1 and the relatively less affected CA3. For comparisons between regions and across disease status, we find consistency in both pathway enrichment as well as specific differentially expressed genes across several studies. Furthermore, genes that show decreased expression with AD progression also tend to show enrichment in CA3 (and vice versa), suggesting that transcription levels in a region may reflect that region's vulnerability to disease. In particular, we find several strong candidate vulnerability (ABCA1, MT1H, PDK4, RHOBTB3) and protection (FAM13A1, LINGO2, UNC13C) genes based on expression patterns. We have also applied weighted gene coexpression network analysis (WGCNA) to explore the pathophysiology of AD from a systems perspective, finding modules for major cell types, which each show distinct disease-relevant expression patterns. In particular, a microglial module shows increased expression in the brain of non-demented controls harboring early NFT pathology, suggesting that microglial activation is an early event in AD progression.
GSE29385 ImmunoHuman 2015Q2 465 15 Febrile patients PCR positive for H1N1 swine flu, seasonal H1N1 and seasonal H3N2 in nasal swabs and controls consisting of febrile patients with rhinovirus infection or febrile patients of non-viral etiology (nasal swabs PCR negative for common respiratory viruses and blood PCR negative for dengue and parvovirus B19) were assessed consecutively for global transcriptional changes in whole blood
GSE29536 ImmunoHuman SLE 410 4 This dataset was used to establish whole blood transcriptional modules (n=260) that represent groups of coordinately expressed transcripts that exhibit altered abundance within individual datasets or across multiple datasets. This modular framework was generated to reduce the dimensionality of whole blood microarray data processed on the Illumina Beadchip platform yielding data-driven transcriptional modules with biologic meaning.
GSE29615 ImmunoHuman 2015Q2 83 2 Systems vaccinology has emerged as an interdisciplinary field that combines systems wide measurements and network and predictive modeling applied to vaccinology.\r\nHere we used the systems vaccinology approach to study the molecular mechanisms underlying the innate responses to the trivalent inactivated influenza (TIV) and live attenuated influenza (LAIV) vaccination in humans, and to identify early gene signatures that predict the magnitude of the antibody responses to influenza vaccination.
GSE29617 ImmunoHuman 2015Q2 80 2 Systems vaccinology has emerged as an interdisciplinary field that combines systems wide measurements and network and predictive modeling applied to vaccinology.\r\nHere we used the systems vaccinology approach to study the molecular mechanisms underlying the innate responses to the trivalent inactivated influenza (TIV) and live attenuated influenza (LAIV) vaccination in humans, and to identify early gene signatures that predict the magnitude of the antibody responses to influenza vaccination.
GSE29618 ImmunoHuman 2015Q2 84 8 Systems vaccinology has emerged as an interdisciplinary field that combines systems wide measurements and network and predictive modeling applied to vaccinology.\r\nHere we used the systems vaccinology approach to study the molecular mechanisms underlying the innate responses to the trivalent inactivated influenza (TIV) and live attenuated influenza (LAIV) vaccination in humans, and to identify early gene signatures that predict the magnitude of the antibody responses to influenza vaccination.
GSE29652 ImmunoHuman AD 18 3 Astrocyte dysfunction impacts their normal function, including neuronal support, thereby contributing to neurodegenerative pathologies including Alzheimer's disease (AD). Therefore to understand the role of astrocytes in the pathogenesis of age-related disorders we analysed the gene expression profile of astrocytes with respect to Alzheimer-type pathology.\r\nThe aim of the present study was to combine immuno-LCM and microarray analysis to characterise the astrocyte transcriptome at different Braak stages, and with respect to ApoE genotype, in post-mortem human temporal cortex sampled dervied from the Medical Research Council Cognitive Function and Ageing Study (MRC-CFAS).
GSE29680 ImmunoHuman AD 29 3 The hypothesis was that 6 months of dietary n-3 FA supplementation to humans affected expression of genes that might be of significance for inflammatory processes and for Alzheimer´s disease.
GSE29746 ImmunoHuman Arthritis 31 0 The aim of this study was to compare gene expression between two pathological groups of human synovial fibroblasts (SF) from rheumatoid arthritis (RA) and osteoarthritis (OA) synovial tissues with normal SF from healthy individuals (HSF). We used microarray expression profiling in SF cultured from OA, RA and normal synovial tissues. We found larger numbers of transcripts with differential expression in OASF compared to the other groups than in RASF compared to HSF. This data demonstrate that cultured OASF display a more robust transcriptomic profile than RASF when compared to HSF.
GSE29773 ImmunoHuman PD 12 3 Patient-specific induced pluripotent stem cells (iPSCs) derived from somatic cells provide a unique tool for the study of human disease in disease relevant cells, as well as a promising source for cell replacement therapies for degenerative diseases. However one of the crucial limitations before realizing the full promise of this “disease in a dish” approach has been the inability to do controlled experiments under genetically defined conditions. This is particularly relevant for disorders with long latency periods, such as Parkinson’s disease (PD), where in vitro phenotypes of patient-derived iPSCs are predicted to be subtle and susceptible to significant epistatic effects of genetic background variations. By combining zinc-finger nuclease (ZFN)-mediated genome editing and iPSC technology we provide a generally applicable solution to this key problem by generating isogenic pairs of disease and control human embryonic stem cells (hESCs) and hiPSCs lines that differ exclusively at a susceptibility variant for PD by modifying a single point mutation (A53T) in the a-synuclein gene. The robust capability to genetically correct disease causing point mutations in patient-derived hiPSCs represents not only a significant progress for basic biomedical research but also a major advancement towards hiPSC-based cell replacement therapies using autologous cells.
GSE2980 ImmunoHuman LungDisease 18 4 Mutations in the gene encoding surfactant protein C (SFTPC) have been linked to interstitial lung disease in children and adults. Expression of the index mutation, SP-Cdeltaexon4, in transiently transfected cells and type II cells of transgenic mice resulted in misfolding of the proprotein, activation of ER stress pathways and cytotoxicity. In the current study we show that stably transfected cells adapted to chronic ER stress imposed by constitutive expression of SP-Cdeltaexon4 via an NF-kB-dependent pathway. However, infection of cells expressing SP-Cdeltaexon4 with respiratory syncytial virus resulted in significantly enhanced cytotoxicity associated with accumulation of the mutant proprotein, pronounced activation of the unfolded protein response and cell death. Adaptation to chronic ER stress imposed by misfolded SP-C was associated with increased susceptibility to viral-induced cell death. The wide variability in the age of onset of ILD in patients with SFTPC mutations may be related to exposure to an environmental insult that ultimately overwhelms the homeostatic, cytoprotective response.
GSE30023 ImmunoHuman Arthritis 12 2 Comparative gene expression profiling of mononuclear cells from synovial fluid samples of rheumatoid arthritis (RA) and\r\nspondyloarthropathy (SpA) cases was performed. A total of 72 transcripts were found to be differentially expressed in RA compared\r\nto SpA, with p-value threshold of 0.05 and using the Benjamini-Hochberg False Discovery rate multiple comparison corrections.\r\nFrom the list, 57 transcripts were found to be upregulated in RA as compared to SpA and 15 downregulated by a fold\r\nchange cut-off of 1.5-fold.
GSE30027 ImmunoHuman COPD 12 3 It is unknown whether human lung T cells recirculate or belong to a distinct tissue-specific population. This issue is important for understanding their role in protection against viral infection and their contribution to pathophysiology of lung diseases such as chronic obstructive pulmonary disease. By comparing transcriptional profiles of blood and lung CD8+ T cells, we aimed to reveal specific traits of lung CD8+ T cells.
GSE3004 ImmunoHuman Asthma 10 1 Allergen exposure induces the airway epithelium to produce chemoattractants, proallergic interleukins, matrix-modifying proteins, and proteins that influence the growth and activation state of airway structural cells. These proteins, in turn, contribute to the influx of inflammatory cells and changes in structure that characterize the asthmatic airway. To use the response of the airway epithelium to allergen to identify genes not previously associated with allergic responses, we compared gene expression in cytokeratin-positive cells before and after segmental allergen challenge. After challenge with concentrations of allergen in the clinically relevant range, 755 (6%) of the detectable sequences had geometric mean fold-changes in expression, with 95% confidence intervals that excluded unity. Using a prospectively defined conservative filtering algorithm, we identified 141 sequences as upregulated and eight as downregulated, with confirmation by conventional polymerase chain reaction in all 10 sequences studied. Using this approach, we identified asthma-associated sequences including interleukin (IL-)-3, IL-4, and IL-5 receptor subunits, the p65 component of nuclear factor-kappaB, and lipocortin. The genomic response of the human airway to concentrations of allergen in the clinically relevant range involves a greater number of genes than previously recognized, including many not previously associated with asthma that are differentially expressed after airway allergen exposure.
GSE30059 ImmunoHuman 2015Q2 72 8 The objective of this study is to: 1) Characterize the cellular origin of transciptional signatures observed on day 1 after vaccination with 2009/10 seasonal influenza and pneumococcal vaccine discovered by transcriptional profiling of whole blood samples in data set “WholeBlood_SysVax”. 2) Discover potential biomarkers for immune-responsiveness to non-live vaccines.
GSE30063 ImmunoHuman COPD 169 2 The toll-like receptors (TLRs) are important components of the respiratory epithelium host innate defense, enabling the airway surface to recognize and respond to a variety of insults in inhaled air. Based on the knowledge that smokers are more susceptible to pulmonary infection and the airway epithelium of smokers with chronic obstructive pulmonary disease (COPD) is characterized by bacterial colonization and acute exacerbation of airway infections, we assessed whether smoking alters the expression of TLRs in human small airway epithelium, the primary site of smoking-induced disease. Microarrays were used to survey the TLR family gene expression in small airway (10th-12th order) epithelium from healthy nonsmokers (n=60), healthy smokers (n=73) and smokers with COPD (n=36). Using the criteria of detection call of present in =50%, 6 of 10 TLRs (1, 2, 3, 4, 5 and 8) were expressed. Compared to nonsmokers, the most strikingly changed gene is TLR5, which down-regulated in healthy smokers (1.4-fold decrease, p<10-13) and in smokers with COPD (1.6-fold, p<10-14). TaqMan RT-PCR confirmed these observations. Bronchial biopsies immunofluorescence showed that TLR5 protein was expressed mainly on the apical side of the human airway epithelium and decreased in healthy smokers and smokers with COPD. In vitro studies showed that the level of TLR5 downstream genes, IL-6 and IL-8 were highly induced in TLR5 high-expressing cells compared to TLR5 low-expressing cells after flagellin exposure. In the context that TLR5 functions to recognize pathogens and activate innate immune responses, the smoking-induced down-regulation of TLR5 likely contributes to smoking-related susceptibility to airway infection.
GSE30153 ImmunoHuman SLE 26 1 Systemic lupus erythematosous (SLE) is an autoimmune disease with an important clinical and biological heterogeneity. B lymphocytes appear central to the development of SLE which is characterized by the production of a large variety of autoantibodies and hypergammaglobulinemia. In mice, immature B cells from spontaneous lupus prone animals are able to produce autoantibodies when transferred into immunodeficient mice, strongly suggesting the existence of intrinsic B cell defects during lupus. In order to approach these defects in humans, we compared the peripheral B cell transcriptomes of quiescent lupus patients to normal B cell transcriptomes. Peripheral blood was drawn into heparin-containing sterile tubes and peripheral blood mononuclear cells were prepared by Ficoll (Amersham) density gradient centrifugation for immediate use. B cells were labeled with a biotin anti-CD19 monoclonal antibody (HIB19 clone, Pharmingen) at 4°C
GSE30180 ImmunoHuman LungDisease 10 1 A proper understanding of the mechanisms underlying crystalline silica-induced pulmonary toxicity has implications in the management and potential prevention of the adverse health effects associated with silica exposure including silicosis, cancer and several auto-immune diseases. Human lung type II epithelial cells and rat lungs exposed to crystalline silica were employed as experimental models to determine global gene expression changes in order to understand the molecular mechanisms underlying silica-induced pulmonary toxicity. The differential gene expression profile induced by silica correlated with its toxicity in the A549 cells. The biological processes perturbed by silica exposure in the A549 cells and rat lungs, as identified by the bioinformatic analysis of the differentially expressed genes, demonstrated significant similarity. Functional categorization of the differentially expressed genes identified cancer, cellular movement, cellular growth and proliferation, cell death, inflammatory response, cell cycle, cellular development, and genetic disorder as top-ranking biological functions perturbed by silica exposure in the A549 cells and rat lungs. The involvement of oxidative stress and apoptosis in the silica-induced pulmonary toxicity was confirmed by ELISA and confocal microscopy analysis, respectively, of the silica-exposed A549 cells. Results of our study, in addition to confirming several previously identified molecular targets and mechanisms involved in silica toxicity, identified novel molecular targets and mechanisms potentially involved in silica-induced pulmonary toxicity. Further investigations, including those focused on the novel molecular targets and mechanisms identified in the current study, may result in a better management and, possibly, reduction and/or prevention of the potential adverse health effects associated with crystalline silica exposure.
GSE30200 ImmunoHuman LungDisease 20 4 A proper understanding of the mechanisms underlying crystalline silica-induced pulmonary toxicity has implications in the management and potential prevention of the adverse health effects associated with silica exposure including silicosis, cancer and several auto-immune diseases. Human lung type II epithelial cells and rat lungs exposed to crystalline silica were employed as experimental models to determine global gene expression changes in order to understand the molecular mechanisms underlying silica-induced pulmonary toxicity. The differential gene expression profile induced by silica correlated with its toxicity in the A549 cells. The biological processes perturbed by silica exposure in the A549 cells and rat lungs, as identified by the bioinformatic analysis of the differentially expressed genes, demonstrated significant similarity. Functional categorization of the differentially expressed genes identified cancer, cellular movement, cellular growth and proliferation, cell death, inflammatory response, cell cycle, cellular development, and genetic disorder as top-ranking biological functions perturbed by silica exposure in the A549 cells and rat lungs. The involvement of oxidative stress and apoptosis in the silica-induced pulmonary toxicity was confirmed by ELISA and confocal microscopy analysis, respectively, of the silica-exposed A549 cells. Results of our study, in addition to confirming several previously identified molecular targets and mechanisms involved in silica toxicity, identified novel molecular targets and mechanisms potentially involved in silica-induced pulmonary toxicity. Further investigations, including those focused on the novel molecular targets and mechanisms identified in the current study, may result in a better management and, possibly, reduction and/or prevention of the potential adverse health effects associated with crystalline silica exposure.
GSE30213 ImmunoHuman LungDisease 10 1 A proper understanding of the mechanisms underlying crystalline silica-induced pulmonary toxicity has implications in the management and potential prevention of the adverse health effects associated with silica exposure including silicosis, cancer and several auto-immune diseases. Human lung type II epithelial cells and rat lungs exposed to crystalline silica were employed as experimental models to determine global gene expression changes in order to understand the molecular mechanisms underlying silica-induced pulmonary toxicity. The differential gene expression profile induced by silica correlated with its toxicity in the A549 cells. The biological processes perturbed by silica exposure in the A549 cells and rat lungs, as identified by the bioinformatic analysis of the differentially expressed genes, demonstrated significant similarity. Functional categorization of the differentially expressed genes identified cancer, cellular movement, cellular growth and proliferation, cell death, inflammatory response, cell cycle, cellular development, and genetic disorder as top-ranking biological functions perturbed by silica exposure in the A549 cells and rat lungs. The involvement of oxidative stress and apoptosis in the silica-induced pulmonary toxicity was confirmed by ELISA and confocal microscopy analysis, respectively, of the silica-exposed A549 cells. Results of our study, in addition to confirming several previously identified molecular targets and mechanisms involved in silica toxicity, identified novel molecular targets and mechanisms potentially involved in silica-induced pulmonary toxicity. Further investigations, including those focused on the novel molecular targets and mechanisms identified in the current study, may result in a better management and, possibly, reduction and/or prevention of the potential adverse health effects associated with crystalline silica exposure.
GSE30214 ImmunoHuman LungDisease 10 1 A proper understanding of the mechanisms underlying crystalline silica-induced pulmonary toxicity has implications in the management and potential prevention of the adverse health effects associated with silica exposure including silicosis, cancer and several auto-immune diseases. Human lung type II epithelial cells and rat lungs exposed to crystalline silica were employed as experimental models to determine global gene expression changes in order to understand the molecular mechanisms underlying silica-induced pulmonary toxicity. The differential gene expression profile induced by silica correlated with its toxicity in the A549 cells. The biological processes perturbed by silica exposure in the A549 cells and rat lungs, as identified by the bioinformatic analysis of the differentially expressed genes, demonstrated significant similarity. Functional categorization of the differentially expressed genes identified cancer, cellular movement, cellular growth and proliferation, cell death, inflammatory response, cell cycle, cellular development, and genetic disorder as top-ranking biological functions perturbed by silica exposure in the A549 cells and rat lungs. The involvement of oxidative stress and apoptosis in the silica-induced pulmonary toxicity was confirmed by ELISA and confocal microscopy analysis, respectively, of the silica-exposed A549 cells. Results of our study, in addition to confirming several previously identified molecular targets and mechanisms involved in silica toxicity, identified novel molecular targets and mechanisms potentially involved in silica-induced pulmonary toxicity. Further investigations, including those focused on the novel molecular targets and mechanisms identified in the current study, may result in a better management and, possibly, reduction and/or prevention of the potential adverse health effects associated with crystalline silica exposure.
GSE30215 ImmunoHuman LungDisease 10 1 A proper understanding of the mechanisms underlying crystalline silica-induced pulmonary toxicity has implications in the management and potential prevention of the adverse health effects associated with silica exposure including silicosis, cancer and several auto-immune diseases. Human lung type II epithelial cells and rat lungs exposed to crystalline silica were employed as experimental models to determine global gene expression changes in order to understand the molecular mechanisms underlying silica-induced pulmonary toxicity. The differential gene expression profile induced by silica correlated with its toxicity in the A549 cells. The biological processes perturbed by silica exposure in the A549 cells and rat lungs, as identified by the bioinformatic analysis of the differentially expressed genes, demonstrated significant similarity. Functional categorization of the differentially expressed genes identified cancer, cellular movement, cellular growth and proliferation, cell death, inflammatory response, cell cycle, cellular development, and genetic disorder as top-ranking biological functions perturbed by silica exposure in the A549 cells and rat lungs. The involvement of oxidative stress and apoptosis in the silica-induced pulmonary toxicity was confirmed by ELISA and confocal microscopy analysis, respectively, of the silica-exposed A549 cells. Results of our study, in addition to confirming several previously identified molecular targets and mechanisms involved in silica toxicity, identified novel molecular targets and mechanisms potentially involved in silica-induced pulmonary toxicity. Further investigations, including those focused on the novel molecular targets and mechanisms identified in the current study, may result in a better management and, possibly, reduction and/or prevention of the potential adverse health effects associated with crystalline silica exposure.
GSE30326 ImmunoHuman Asthma 32 1 Global patterns of gene expression was profiled in nasal lavage samples obtained from asthmatic children during an acute Picornavirus-induced exacerbation and 7-14 days later.\r\nGene coexpression network analysis and prior knowledge was employed to reconstruct the wiring diagram of the underlying gene networks.
GSE30550 ImmunoHuman 2015Q2 268 30 The transcriptional responses of human hosts towards influenza viral pathogens are important for understanding virus-mediated immunopathology. Despite great advances gained through studies using model organisms, the complete temporal host transcriptional responses in a natural human system are poorly understood. In a human challenge study using live influenza (H3N2/Wisconsin) viruses, we conducted a clinically uninformed (unsupervised) factor analysis on gene expression profiles and established an ab initio molecular signature that strongly correlates to symptomatic clinical disease. This is followed by the identification of 42 biomarkers whose expression patterns best differentiate early from late phases of infection. In parallel, a clinically informed (supervised) analysis revealed over-stimulation of multiple viral sensing pathways in symptomatic hosts and linked their temporal trajectory with development of diverse clinical signs and symptoms. The resultant inflammatory cytokine profiles were shown to contribute to the pathogenesis because their significant increase preceded disease manifestation by 36 hours. In subclinical asymptomatic hosts, we discovered strong transcriptional regulation of genes involved in inflammasome activation, genes encoding virus interacting proteins, and evidence of active anti-oxidant and cell-mediated innate immune response. Taken together, our findings offer insights into influenza virus-induced pathogenesis and provide a valuable tool for disease monitoring and management in natural environments.
GSE30664 ImmunoHuman NormalControl 8 2 Human T cell clones were derived according to standard protocols using different mix of cytokines, once assessed for their functional profile were studied for gene expression. The purpose of this study is to analyze human Th1 and Th17 clones with and without stimulation with PMA and Ionomycin to measure differences in gene expression that can distinguish the two lineages.
GSE30674 ImmunoHuman NormalControl 56 24 T lymphocytes are orchestrators of adaptive immunity. Naïve T cells may differentiate into the Th1, Th2, Th17 or iTreg phenotype, depending on environmental co-stimulatory signals. In order to identify the genes and pathways involved in differentiation of Jurkat T cells towards Th1 and Th2 subtypes we performed comprehensive transcriptome analyses of Jurkat T cells stimulated with various stimuli an pathway inhibitors
GSE30697 ImmunoHuman Asthma 95 2 Recent genome-wide association studies (GWAS) have identified a number of novel genetic associations with complex human diseases. In spite of these successes, results from GWAS generally explain only a small proportion of disease heritability, an observation termed the “missing heritability problem.” Several sources for the missing heritability have been proposed, including the contribution of many common variants with small individual effect sizes, which cannot be reliably found using the standard GWAS approach. The goal of our study was to explore a complementary approach, which combines GWAS results with functional data in order to identify novel genetic associations with small effect sizes. To do so, we conducted a GWAS for lymphocyte count, a physiologic quantitative trait associated with asthma, in 462 Hutterites. In parallel, we performed a genome-wide gene expression study in lymphoblastoid cell lines (LCLs) from 96 Hutterites. We found significant support for genetic associations using the GWAS data when we considered variants near the 193 genes whose expression levels across individuals were most correlated with lymphocyte counts. Interestingly, these variants are also enriched with signatures of an association with asthma susceptibility, an observation we were able to replicate. The associated loci include genes previously implicated in asthma susceptibility, as well as novel candidate genes enriched for functions related to T cell receptor signaling and ATP synthesis. Our results, therefore, establish a new set of asthma susceptibility candidate genes. More generally, our observations support the notion that many loci of small effects influence variation in lymphocyte count and asthma susceptibility.
GSE30768 ImmunoHuman Psoriasis 14 2 To understand the development of new psoriasis lesions, we studied a group of moderate-to-severe psoriasis patients who experienced a relapse after ceasing efalizumab (anti-CD11a, Raptiva, Genentech). There were increased CD3+ T cells, neutrophils, CD11c+ and CD83+ myeloid DCs, but no increase in CD1c+ resident myeloid DCs. In relapsed lesions, there were many CD11c+CD1c-, inflammatory myeloid DCs identified by TNFSF10/TRAIL, TNF, and iNOS. CD11c+ cells in relapsed lesions co-expressed CD14 and CD16 in situ. Efalizumab induced an improvement in many psoriasis genes, and during relapse, the majority of these genes reversed back to a lesional state. Gene Set Enrichment Analysis (GSEA) of the transcriptome of relapsed tissue showed that many of the gene sets known to be present in psoriasis were also highly enriched in relapse. Hence, on ceasing efalizumab, T cells and myeloid cells rapidly enter the skin to cause classic psoriasis.
GSE30999 ImmunoHuman Psoriasis 170 1 A gene expression profiling sub-study was conducted in which skin biopsy samples were collected from 85 patients with moderate-to-severe psoriasis who were participating in ACCEPT, an IRB-approved Phase 3, multicenter, randomized trial. This analysis identified 4,175 probe-sets as being significantly modulated in psoriasis lesions (LS) compared with matched biopsies of non-lesional (NL) skin.
GSE31469 ImmunoHuman Influenza 12 3 We used the microarray data to analyze host cells response on A549 cells infected with A/WSN/33 (H1N1)
GSE31470 ImmunoHuman Influenza 6 1 We used the microarray data to analyze host cells response on A549 cells infected with A/WSN/33 (H1N1)
GSE31471 ImmunoHuman Influenza 18 5 We used the microarray data to analyze host cells response on A549 cells infected with A/Duck/Malaysia/01 (H9N2)
GSE31472 ImmunoHuman Influenza 18 5 We used the microarray data to analyze host cells response on A549 cells infected with A/duck/Malaysia/F118/08/2004(H5N2)
GSE31473 ImmunoHuman Influenza 6 1 We used the microarray data to analyze host cells response on A549 cells infected with A/duck/Malaysia/F59/04/1998(H5N2)
GSE31474 ImmunoHuman Influenza 6 1 We used the microarray data to analyze host cells response on A549 cells infected with A/duck/Malaysia/F189/07/2004(H5N2)
GSE31475 ImmunoHuman Influenza 6 1 We used the microarray data to analyze host cells response on A549 cells infected with A/duck/Malaysia/F119/3/1997(H5N3)
GSE31518 ImmunoHuman Influenza 18 5 We used the microarray data to analyze host cells response on A549 cells infected with Influenza A virus (A/Singapore/478/2009 (pH1N1))
GSE31524 ImmunoHuman nomodel 84 0 This SuperSeries is composed of the SubSeries listed below.
GSE31652 ImmunoHuman Psoriasis 30 4 In psoriasis, inflammation and epidermal hyperplasia are thought to be controlled by T cell-derived cytokines. Evidence now suggests that Th17 and Th22 cells infiltrate psoriasis lesions and by secreting IL-17 and IL-22, respectively, may drive disease-specific gene or cell responses. While studies in model systems indicate that IL-22 has a dominant pathogenic role, there is evolving evidence that IL-17 contributes to features of psoriasis. To more fully understand the role of IL-17 in human disease pathogenesis, we examined psoriatic skin lesions obtained from patients treated with an anti-IL-17 (IL-17 A) monoclonal antibody, LY2439821. In a phase 1, randomized, double-blind, placebo-controlled dose escalation trial, patients with chronic psoriasis were randomized to receive 3 doses of subcutaneous LY2439821 at 5 mg (n=8), 15 mg (n=8), 50 mg (n=8), 150 mg (n=8) or placebo (n=8) at weeks 0, 2 and 4. Repeat biopsies were taken from the same lesional area at baseline, week 2 and 6. At week 6, a PASI75 was observed in 0/8, 2/8, 5/7 and 8/8 patients receiving 5 mg, 15 mg, 50 mg or 150 mg LY2439821 respectively and 0/8 patients receiving placebo. The antibody was well-tolerated. In patients receiving the two highest doses, histological and immunohistochemical analyses of biopsies revealed significant reductions from baseline in keratinocyte proliferation, hyperplasia and epidermal thickness after 2 weeks, as well as reduced infiltration into the dermis and epidermis by T-cells (CD3+) and dendritic cells (CD11c and DC-LAMP). Keratinocyte expression of innate defense proteins, S100A7, S100A8, beta-defensin2 and LL37/cathelicidin was also reduced. By week 6, the skin appeared normal with a reversal of disease defining pathological features. Quantitative RT-PCR revealed decreased expression of interferon gamma (IFN-gamma), IL-22 and IL-17, key cytokines from T cell subsets Th1, Th22 and Th17, respectively. In order to explore the extent to which IL-17 blockade influences an even broader set of inflammatory or psoriatic disease related genes, mRNA levels from skin biopsy samples were evaluated using whole genome microarrays. At week 2, the highest dose of LY2439821 modulated over 1500 genes significantly (>1.5 fold change [FC], p<0.05). Of these, 51 genes were strongly suppressed (>7-fold) including IL-19, lipocalin, amphiregulin, granzyme B, and several chemokines. In a separate analysis, those genes known to be synergistically regulated by both IL-17 and TNF-alpha showed the greatest normalization in expression compared to genes known to be regulated by TNF-alpha alone, IFN-gamma or Interferon alpha. Our data suggest that Th17 cells, through the expression of IL-17, mediate psoriasis pathogenesis, and that neutralization of IL-17 with LY2439821 suppresses signaling through multiple inflammatory circuits by inhibiting expression of cytokines from multiple T cell subsets, as well as chemokines, and antimicrobial proteins from keratinocytes.
GSE31685 ImmunoHuman Arthritis 6 1 The aim of our study is to increase understanding of the antiproliferative and pro-apoptotic potency of resveratrol by identifying genes which underlie involved pathological pathways and biological process. Therefore, we performed a gene Chip Transcription Analysis with subsequent Protein ANalysis THrough Evolutionary Relationships (PANTHER) analysis to evaluate which transcripted genes are significantly influenced by resveratrol.
GSE31773 ImmunoHuman Asthma 40 4 Comparison of mRNA expression showed widespread changes in the circulating CD8+ but not CD4+ T-cells from patients with severe asthma. No changes were observed in the CD4+ and CD8+ T-cells in non-severe asthmatics versus healthy controls. Bioinformatics analysis showed that the changes in CD8+ T-cell mRNA expression were associated with multiple pathways involved in T-cell activation. As with mRNAs, we also observed widespread changes in expression of non-coding RNA species including natural antisense, pseudogenes, intronic long ncRNAs and long intergenic long ncRNAs in CD8+ T-cells from severe asthmatics. Measurement of the miRNA expression profile showed selective down-regulation of miR-28-5p in CD8+ T-cells and reduction of miR-146a and miR-146b in both CD4+ and CD8+ T-cells.
GSE3183 ImmunoHuman Asthma 15 3 The purpose of this project is to gain a better understanding of the early cytokine-mediated mechanisms that lead to asthma.
GSE32008 ImmunoHuman Arthritis 12 2 Methotrexate (MTX) is an anti-folate drug used to treat inflammatory diseases such as rheumatoid arthritis. The changes induced by MTX were profiled within EA.hy 926 cells grown in normal (Hi) and low (Lo) folate. Several inflammatory genes were up regulated and several mitosis related genes were down regulated.
GSE3212 ImmunoHuman COPD 10 1 Cigarette smoking is the leading cause of the respiratory diseases collectively known as chronic obstructive pulmonary disease (COPD). While the pathogenesis of COPD is complex, there is abundant evidence that alveolar macrophages (AM) play an important role. Based on the concept that COPD is a slow-progressing disorder likely involving multiple mediators released by AM activated by cigarette smoke, the present study focuses on the identification of previously unrecognized genes that may be linked to early events in the molecular pathogenesis of COPD, as opposed to factors associated with the presence of disease. To accomplish this, microarray analysis using Affymetrix microarrays was used to carry out an unbiased survey of the differences in gene expression profiles in the AM of phenotypically normal, ~20 pack-yr smokers compared to healthy non-smokers. Although smoking did not alter the global gene expression pattern of AM, 75 genes were modulated by smoking, with 40 genes up-regulated and 35 down-regulated in the AM of smokers compared to non-smokers. Most of these genes belong to the functional categories of immune/inflammatory response, cell adhesion and extracellular matrix, proteolysis and antiproteolysis, lysosomal function, antioxidant-related, signal transduction and regulation of transcription. Of these 75 genes, 69 have not been previously recognized to be up- or down-regulated in alveolar macrophages in association with smoking or COPD, including genes coding for proteins belonging to all of the above categories, and others belonging to various functional categories or of unknown function. These observations suggest that gene expression responses of alveolar macrophages associated with the stress of cigarette smoking are more complex than previously thought, and offer a variety of new insights into the complex pathogenesis of smoking-induced lung diseases.
GSE32278 ImmunoHuman SLE 8 3 The goal of this study was to determine what genes are up- and down-regulated in response to lupus immune complexes in purified CD14+ monocyte stimulations. Our results have shown that novel genes are induced by immune complexes but the response is less robust when using purified monocytes versus total PBMCs
GSE32279 ImmunoHuman SLE 8 3 The goal of this study was to determine what genes are up- and down-regulated in response to lupus immune complexes in total peripheral blood mononuclear cells (PBMCs). Our results have shown that novel genes are induced by immune complexes that are likely important for lupus pathogenesis plus that C1q regulates these pathways and induces multiple new pathways not previously identified.
GSE32282 ImmunoHuman BasicScience 12 3 We performed gene expression microarray experiments to compare the global transcriptional response induced by b-glucans and LPS with their secretomes. We identified 1683, 767 and 1447 genes with over two-fold increase or decrease in LPS-, curdlan- or GBY-stimulated macrophages, respectively. We show that both LPS and b-glucan induces significant gene expression changes in macrophages, but only b-glucans activate a robust protein secretion.
GSE32317 ImmunoHuman Arthritis 19 1 Osteoarthritis is characterized by degeneration of cartilage and bone in the synovial joints. Recent findings suggest that inflammation may play a role in osteoarthritis, with synovitis being associated with the clinical symptoms of osteoarthritis. Furthermore, we have found that levels of inflammatory complement components are abnormally high in the synovial fluid of individuals with osteoarthritis.\r\nTo determine whether synovial membranes could be a source of complement and other inflammatory molecules in osteoarthritic joints, we characterized the expression of genes in synovial membranes from patients with early-stage or end-stage osteoarthritis.
GSE32407 ImmunoHuman Psoriasis 60 7 Psoriasis is a chronic, debilitating, immune-mediated inflammatory skin disease. As IFN-? is involved in many cellular processes, including activation of T cells and dendritic cells (DCs), antigen processing and presentation, cell adhesion and trafficking, and cytokine and chemokine production, IFN-?-producing Th1 cells were proposed to be integral to the pathogenesis of psoriasis. Recently, IFN-? was shown to enhance IL-23 and IL-1 production by DCs and subsequently induce Th17 cells, important contributors to the inflammatory cascade in psoriasis lesions. To determine if IFN-? indeed induces the pathways leading to the development of psoriasis lesions, a single intradermal injection of IFN-? was administered to an area of clinically normal, non-lesional skin of psoriasis patients and biopsies were collected 24 hours later. Although there were no visible changes in the skin, IFN-? induced molecular and histological features characteristic of psoriasis lesions. IFN-? increased a number of differentially expressed genes in the skin, including many chemokines concomitant with an influx of T cells and inflammatory DCs. Furthermore, inflammatory DC products TNF, iNOS, IL-23, and TRAIL were present in IFN-?-treated skin. Thus, IFN-?, which is significantly elevated in non-lesional skin compared to healthy skin, appears to be a key pathogenic cytokine that can induce the inflammatory cascade in psoriasis.
GSE32537 ImmunoHuman LungDisease 217 5 Rationale: The fibrosing idiopathic interstitial pneumonias (IIPs) are classified based on clinical, radiographic, and pathologic criteria. The separation into phenotypic subgroups is useful in predicting outcome and therapeutic strategy; however a large degree of ambiguity remains. Gene expression profiling may contribute to traditional criteria in IIPs by characterizing the dynamic biology that more accurately distinguishes subtypes of these diseases or their prognoses.\r\nMethods: We collected transcriptional and miRNA profiles on lung tissue from 167 subjects with IIP and 50 non-diseased controls. Differential expression of individual transcripts and miRNAs was identified using an ANCOVA model incorporating the clinical diagnosis of each subject as well as age, gender, and smoking status. Validation was performed in an independent cohort of 131 IIPs and 39 non-diseased controls.\r\nResults: Our results demonstrate a substantial degree of overlap in mRNA and miRNA signatures of clinical subtypes of IIP. However, we identify two subtypes of IPF/UIP based on a strong molecular signature associated with expression of cilium genes. We demonstrate that elevated expression of cilium genes is associated with more extensive microscopic honeycombing, more fibroblastic foci, higher expression of the airway mucin gene MUC5B, and better survival in an independent cohort of IPF/UIP patients. Moreover, we identify miRNAs involved in the regulation of cilium-associated gene expression that contribute to novel molecular subphenotypes of IPF.\r\nConclusions: While subtypes of IIP are related biologically with similar transcriptional profiles, expression of cilium genes appear to identify two unique clinical presentations of IPF/UIP.
GSE32539 ImmunoHuman PulmonaryFibrosis 217 5 This SuperSeries is composed of the SubSeries listed below.
GSE32591 ImmunoHuman SLE 93 2 Nephritis (LN) is a serious manifestation of SLE. Therapeutic studies in mouse LN models do not always predict outcomes of human therapeutic trials, raising concerns about the human relevance of these models. In this study we used an unbiased transcriptional network approach to define similarities and differences between three lupus models and human LN. Affymetrix-based expression profiles were analyzed using Genomatix Bibliosphere software and transcriptional networks were compared using the Tool for Approximate LargE graph matching (TALE). The 20 network hubs (nodes) shared between all three models and human LN reflect key pathologic processes, namely immune cell infiltration/activation, macrophage/dendritic cell activation, endothelial cell activation/injury and tissue remodeling/fibrosis. Each model also shares unique features with human LN. Pathway analysis of the TALE nodes highlighted macrophage/DC activation as a cross-species shared feature. To distinguish which genes and activation pathways might derive from mononuclear phagocytes in the human kidneys the gene expression profile of isolated NZB/W renal mononuclear cells was compared with human LN kidney profiles. Network analysis of the shared signature highlighted NFkappaB1 and PPARgamma as major hubs in the tubulointerstitial and glomerular networks respectively. Key nodes in the renal macrophage inflammatory response form the basis for further mechanistic and therapeutic studies.\r\nWe used microarrays to analyze the transcriptome of microdissected renal biopsies from patients with lupus nephritis (LN)
GSE32604 ImmunoHuman Influenza 28 7 The extent of lung regeneration following catastrophic damage and the potential role of adult stem cells in such a process remains obscure. Sublethal infection of mice with an H1N1 influenza virus related to that of the 1918 pandemic triggers massive airway damage followed by apparent regeneration. We show here that p63-expressing stem cells in the bronchiolar epithelium undergo rapid proliferation after infection and radiate to interbronchiolar regions of alveolar ablation. Once there, these cells assemble into discrete, Krt5+ pods and initiate expression of markers typical of alveoli. Gene expression profiles of these pods suggest that they are intermediates in the reconstitution of the alveolar-capillary network eradicated by viral infection. The dynamics of this p63-expressing stem cell in lung regeneration mirrors our parallel findings that defined pedigrees of human distal airway stem cells assemble alveoli-like structures in vitro and suggests new therapeutic avenues to acute and chronic airway disease.
GSE32645 ImmunoHuman 2015Q2 12 3 In the present study we addressed several questions related to the mechanisms of cortical injury. We analyzed genome wide gene expression by microarrays, comparing active multiple sclerosis lesions with highly inflammatory lesions of chronic tuberculous meningitis, with neurodegenerative lesions of Alzheimer’s disease and with normal cortex of age matched controls.
GSE32878 ImmunoHuman 2015Q2 6 1 Influenza virus neuraminidase (NA), a type II transmembrane glycoprotein, is transported to the virus assembly site at the plasma membrane and is a major viral envelope component that plays a critical role in the release of progeny virions and in determination of host range restriction. Although signals/sequences in NA for translocation, sorting and raft association have been identified, little is known about the host factors that are involved in regulating the intracellular and cell surface transport of NA. In this report, we have investigated the involvement of Rho family GTPases in NA transport to the cell surface. We found that expression of constitutively active or inactive mutants of RhoA or Rac1 did not significantly affect the amount of NA that reached the cell surface. Interestingly, expression of constitutively active Cdc42 or depletion of the Cdc42-specific GAP, ARHGAP21, promoted the transport of NA to the plasma membranes. By contrast, cells expressing shRNA targrting Cdc42 or overexpressing ARHGAP21 exhibited a significant decrease in the amount of cell surface-localized NA. Furthermore, silencing of Cdc42 or ARHGAP21 had significant effects on influenza A virus replication. Together, our results reveal that ARHGAP21 and Cdc42-based signaling regulates the NA transport and thereby impacts virus replication.\r\nThis microarray experiment was carried out to find out whether Cdc42 and ARHGAP21 expression levels in A549 cell were changed after WSN infection.
GSE32901 ImmunoHuman NormalControl 18 1 In this study, we examined differential gene expression in naïve human CD4+ T cells, as well as in effector Th1, Th17-negative and Th17-enriched CD4- T cell subsets. We observed a marked enrichment for increased gene expression in effector CD4+ T cells compared to naive CD4+ among immune-mediated disease oci genes. Within effector T cells, expression of disease-associated genes was increased in Th17-enriched compared to Th17-negative cells.\r\nWe used microarray to examine the gene expresssion profile and level of human naïve, Th1 and effector T cell subsets.
GSE32915 ImmunoHuman 2015Q2 16 5 In this project we focused on white matter injury in relapsing remitting MS. We concentrated on material obtained from patients who suffered from fulminant active MS to identify possible sources for ROS production in relation to demyelination and neurodegeneration.
GSE32959 ImmunoHuman NormalControl 37 8 The aim of this dataset was to study in detail the transcription kinetics initiated by cytokines IL-12 and IL-4 in early differentiation of Th1 and Th2 cells, respectively.
GSE32988 ImmunoHuman 2015Q2 48 8 Multiple sclerosis is an immune mediated disease of the central nervous system. High-dose immunosuppression therapy followed by autologous hematopoietic stem cell transplantation (HDI/AHSCT) has emerged in the past few years as a new treatment strategy in patients with severe MS and refractory to conventional treatment. We characterized the molecular profile of T cells during immune reconstitution of these patients. Total RNA of CD4+ and CD8+ T cells from eight MS patients before transplantation and four patients at 6 months, 1 and 2 years after transplantation was processed for DNA microarray analysis. We investigated the molecular and biological function of DEG using bioinformatics tools and selected genes involved with immune response to measure quantitative gene expression by Real-time PCR. In CD8+ T cells, we measured the levels of expression of 23 genes modulated after transplantation: nine transcriptional factors (LEF1, FOXD1, CEBPD, JUN, JUNB, RELB, IFI16, AEBP1) including the translational factor PDCD4, the chemokine CCR7 and adhesion molecule L Selectin, three TNF superfamily members (TNFRSF4, TNFRSF19L, LTß), seven genes involved with molecular signaling (SOCS1, SOCS3, DGKH, CSNK1L1, IKBa, IKBß, IKBe), and the immune cell receptors CD47 and SIRPG. In CD4+ T cells, we evaluated the relative level of expression of STAT3, FcRL3, PDCD1, DGKH, CSNK1L1, L Selectin, CCR7 and PIAS3 that were all modulated after transplantation. We found significantly transcriptional changes in both T cells subsets during the first 2 years post-transplantation, but the analysis of CD8+ T cells revealed more extensive changes of genes involved in effector immune responses.
GSE3307 ImmunoHuman ALS 242 24 Summary: Genetic disorders of muscle cause muscular dystrophy, and are some of the most common inborn errors of metabolism. Muscle also rapidly remodels in response to training and innervation. Muscle weakness and wasting is important in such conditions as aging, critical care medicine, space flight, and diabetes. Finally, muscle can also be used to investigate systemic defects, and the compensatory mechansisms invoked by cells to overcome biochemical and genetic abnormalities. Here, we provide a 13 group data set for comparative profiling of human skeletal muscle. Groups studied are: Normal human skeletal muscle, Acute quadriplegic myopathy (AQM; critical care myopathy), Juvenile dermatomyositis (JDM), Amyotophic lateral sclerosis (ALS), spastic paraplegia (SPG4; spastin), Fascioscapulohumeral muscular dystrophy (FSHD), Emery Dreifuss muscular dystrophy (both X linked recessive emerin form; autosomal dominant Lamin A/C form), Becker muscular dystrophy (partial loss of dystrophin), Duchenne muscular dystrophy (complete loss of dystrophin), Calpain 3 (LGMD2A), dysferlin (LGMD2B), FKRP (glycosylation defect; homozygous for a missense mutation). U133A and U133B microarrays are both available.\r\nHypothesis: This data set is able to define biochemical pathways that are either specific for a disease group, or shared between disease groups. For example, this data set has been used to determine the biochemical pathway perturbations that are shared between the two different types of Emery Dreifuss muscular dystrophy (lamin A/C, and emerin).\r\nSpecific Aim: The specific aim of this study is to determine the disease-specific transcriptional profiles of these 13 patient groups, and to determine if these expression fingerprints provide either pathophysiology or diagnostic information for these diseases. Some of the groups in this large data set have been reported previously using U95A microarrays, as follows:\r\nJuvenile dermatomyositis (JDM): Tezak Z, Hoffman EP, Lutz JL, Fedczyna TO, Stephan D, Bremer EG, Krasnoselska-Riz I, Kumar A, Pachman LM. Gene expression profiling in DQA1*0501+ children with untreated dermatomyositis: a novel model of pathogenesis. J Immunol. 2002 Apr 15;168(8):4154-63.\r\nPMID: 11937576\r\nDuchenne muscular dystrophy (DMD) Chen YW, Zhao P, Borup R, Hoffman EP. Expression profiling in the muscular dystrophies: identification of novel aspects of molecular pathophysiology. J Cell Biol. 2000 Dec 11;151(6):1321-36. PMID: 11121445\r\nSpastic paraplegia (SPG4, spastin): Molon A, Di Giovanni S, Chen YW, Clarkson PM, Angelini C, Pegoraro E, Hoffman EP. Large-scale disruption of microtubule pathways in morphologically normal human spastin muscle. Neurology. 2004 Apr 13;62(7):1097-104. PMID: 15079007\r\nAcute quadriplegic myopathy (AQM): Di Giovanni S, Molon A, Broccolini A, Melcon G, Mirabella M, Hoffman EP, Servidei S. Constitutive activation of MAPK cascade in acute quadriplegic myopathy.\r\nAnn Neurol. 2004 Feb;55(2):195-206. PMID: 14755723\r\nFascioscapulohumeral muscular dystrophy (FSHD): Winokur ST, Chen YW, Masny PS, Martin JH, Ehmsen JT, Tapscott SJ, van der Maarel SM, Hayashi Y, Flanigan KM. Expression profiling of FSHD muscle supports a defect in specific stages of myogenic differentiation. Hum Mol Genet. 2003 Nov 15;12(22):2895-907. Epub 2003 Sep 30. PMID: 14519683
GSE3320 ImmunoHuman COPD 11 1 The earliest morphologic evidence of changes in the airways associated with chronic cigarette smoking is in the small airways. To help understand how smoking modifies small airway structure and function, we developed a strategy using fiberoptic bronchoscopy and brushing to sample the human small airway (10th-12th order) bronchial epithelium to assess gene expression (Affymetrix HG-U133A array) in phenotypically normal smokers (n=6, 24 ± 4 pack-yr) compared to matched non-smokers (n=5). Compared to samples from the large (2nd to 3rd order) bronchi, the small airway samples had a higher proportion of ciliated cells, but less basal, undifferentiated, and secretory cells. The small, but not large, airway samples included Clara cells, a cell found only in the small airway epithelium, and the small, but not the large, airway epithelium expressed genes for the surfactant apoproteins. Despite the fact that the smokers were phenotypically normal, analysis of the small airway epithelium of the smokers compared to the non-smokers demonstrated up- and -down-regulation of genes in multiple categories relevant to the pathogenesis of chronic obstructive lung disease (COPD), including genes coding for cytokines/innate immunity, apoptosis, pro-fibrosis, mucin, responses to oxidants and xenobiotics, antiproteases and general cellular processes. In the context that COPD starts in the small airways, these changes in gene expression in the small airway epithelium in phenotypically normal smokers are candidates for the development of therapeutic strategies to prevent the onset of COPD.
GSE33337 ImmunoHuman COPD 8 2 To define the role of microRNAs and their mRNA targets in emphysema severity in COPD patients.
GSE33338 ImmunoHuman COPD 8 2 This SuperSeries is composed of the SubSeries listed below.
GSE33377 ImmunoHuman Arthritis 42 1 Expression profiles of anti-TNF responders were compared to profiles of anti-TNF non-responders in order to identify an expression signature for anti-TNF response
GSE33464 ImmunoHuman 2015Q2 60 4 The purpose of this study was to characterize the transcriptional effects induced by subcutaneous IFN-beta-1a treatment (Rebif, 22 µg or 44 µg three times a week) in patients with relapsing-remitting form of multiple sclerosis (MS). By using Affymetrix DNA microarrays, we obtained genome-wide expression profiles of peripheral blood mononuclear cells from 12 MS patients within the first two years of IFN-beta administration.
GSE33503 ImmunoHuman AD 4 1 Nasu-Hakola disease (NHD), also designated polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), is a rare autosomal recessive disorder characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by a loss-of-function mutation of DAP12 or TREM2. TREM2 and DAP12 constitute a receptor/adaptor complex expressed on osteoclasts, dendritic cells, macrophages, monocytes, and microglia. At present, the precise molecular mechanisms underlying development of leukoencephalopathy and bone cysts in NHD remain largely unknown. We established THP-1 human monocyte clones that stably express small interfering RNA (siRNA) targeting DAP12 for serving as a cellular model of NHD. Genome-wide transcriptome analysis identified a set of 22 genes consistently downregulated in DAP12 knockdown cells. They constituted the molecular network closely related to the network defined by cell-to-cell signaling and interaction, hematological system development and function, and inflammatory response, where NF-kappaB acts as a central regulator. These results suggest that a molecular defect of DAP12 in human monocytes deregulates the gene network pivotal for maintenance of myeloid cell function in NHD. We found that both DAP12 knockdown and control clones were capable of equally responding to phorbol 12-myristate 13-acetate (PMA), a known inducer of morphological differentiation of THP-1 cells, by exhibiting almost similar gene expression profiles between both, following a 24-hour exposure to 50 nM PMA.
GSE33566 ImmunoHuman LungDisease 123 1 Peripheral blood biomarkers are needed to identify and determine the extent of idiopathic pulmonary fibrosis (IPF). Current physiologic and radiographic prognostic indicators diagnose IPF too late in the course of disease. These results demonstrate that the peripheral blood transcriptome can distinguish normal individuals from patients with IPF, as well as extent of disease when samples were classified by percent predicted DLCO, but not FVC.
GSE3365 ImmunoHuman IBD 127 2 Comparison of PBMC transcriptional profiles in healthy subjects, patients with Crohn's Disease, and patients with Ulcerative Colitis
GSE33943 ImmunoHuman IBD 58 1 Clinical remission is apparent when laboratory markers of inflammation are normal and clinical symptoms are absent. However, sub-clinical inflammation can still be present. A detailed analysis of the immune status during this inactive state of disease may provide a useful tool to subcategorize patients with subclinical immune activation\r\nWe performed (un)supervised clustering analysis of IBD-associated genes and applied Ingenuity® pathway software to identify specific molecular profiles between patients.
GSE34156 ImmunoHuman Inflammation 45 6 human blood monocytes were isolated, activated and harvested at several timepoints\r\nIn this study, we identified genes that were differentially expressed in human monocytes activated with eiter NOD2L and/or TLR2/1L.
GSE34160 ImmunoHuman Asthma 18 4 To determine differential gene expression in peripheral blood of asthmatic individuals undergoing allergen inhalation challenge, post-challenge compared to pre-challenge
GSE34205 ImmunoHuman 2015Q2 101 2 To study the transcriptional profile of patients with acute RSV or Influenza infection,children of median age 2.4 months (range 1.5-8.6) hospitalized with acute RSV and influenza virus infection were offered study enrollment after microbiologic confirmation of the diagnosis. Blood samples were collected from them within 42-72 hours of hospitalization. We excluded children with suspected or proven polymicrobial infections, with underlying chronic medical conditions (i.e congenital heart disease, renal insufficiency), with immunodeficiency, or those who received systemic steroids or other immunomodulatory therapies. The RSV cohort consisted of 51 patients with median age of 2 months (range 1.5-3.9) and the influenza cohort had 28 patients with median age of 5.5 months (range 1.4-21). Control samples were obtained from healthy children undergoing elective surgical procedures or at outpatient clinic visits. To exclude viral co-infections we performed nasopharyngeal viral cultures of all subjects. We recruited 10 control patients for the RSV cohort with median age of 6.7 months (range 5-10), and 12 control patients for the influenza cohort with median age of18.5 months (range 10.5-26).
GSE34248 ImmunoHuman Psoriasis 28 1 To explore the psoriasis phenotype, we characterize gene expression in lesional and non-lesional skin from psoriasis patients.
GSE34313 ImmunoHuman Asthma 10 2 Glucocorticoids, which activate glucocorticoid receptor signaling and thus modulate gene expression, are widely used to treat asthma. Glucocorticoids exert their therapeutic effects in part through modulating airway smooth muscle structure and function. However, the effects of genes that are regulated by GCs on airway function are not fully understood. Here, we used transcription profiling to characterize the effects of a potent glucocorticoid, dexamethasone, on cultured human airway smooth muscle gene expression at 4 and 24 hours.
GSE34516 ImmunoHuman PD 10 2 LRRK2 mutations are the most common genetic cause of Parkinson’s disease (PD). We performed a whole-genome RNA profiling of locus coeruleus post-mortem tissue from idiopathic PD (IPD) and LRRK2-associated PD patients. The differentially expressed genes found in IPD and LRRK2-associated PD were involved in the gene ontology terms of synaptic transmission and neuron projection. In addition, in the IPD group we found associated genes belonging to the immune system. Pathway analysis of the differentially expressed genes in IPD was related with neuroactive-ligand receptor interaction and with immune system pathways. Specifically, the analysis highlighted differential expression of genes located in the chromosome 6p21.3 belonging to the class II HLA. Our findings support the hypothesis of a potential role of neuroinflammation and the involvement of the HLA genetic area in IPD pathogenesis. Future studies are necessary to shed light on the relation of immune system related pathways in the etiopathogenesis of PD.
GSE34562 ImmunoHuman Asthma 6 2 We found a unique subset of effector memory (EM) CD8+ T cells that expressed high levels of IL-6 receptor in human peripheral blood. These cells which also expressed high levels of IL-7Ra (referred to as IL-6R high IL-7Rahigh cells) had the a distinct gene expression profile and cellular characteristics compared to other EM CD8+ T cells. IL-6R high IL-7Ra high cells were early differentiated EM CD8+ T cells with decreased expression of T-bet, KLRG1, perforin and granzyme B. These cells had increased cell proliferation likely secondary to enhanced IL-2 production and high affinity IL-2R expression. IL-6R high IL-7Ra high EM CD8+ T cells exclusively produced high levels of IL-2, IL-5, IL-9 and IL-13 although IFN-r was produced by this cell subset and other EM CD8+ T cells. Of interest, IL-6R high IL-7Ra high EM CD8+ T cells expanded in the peripheral blood of patients with chronic obstructive pulmonary disease (COPD) and asthma where CD8+ T cells, IL-13 and IFN-r are suggested to be involved in the pathogenesis. Being the early-differentiated EM CD8+ T cells with a potent capacity to proliferate, survive and generate multiple cytokines, IL-6R high IL-7Ra high EM CD8+ T cells may serve as a primary reservoir for effector CD8+ T cells which potently expand and produce cytokines upon immune stimulation.
GSE34818 ImmunoHuman PulmonaryFibrosis 14 6 Idiopathic pulmonary fibrosis (IPF) is a chronic and often fatal pulmonary disorder characterized by fibroblast proliferation and the excess deposit of extracellular matrix proteins. The etiology of IPF is unknown, but a central role for microRNAs (miRNAs), a class of small non-coding regulatory RNAs, has been recently suggested. We report the upregulation of miR-199a-5p in mouse lungs undergoing bleomycin-induced fibrosis and also in human biopsies from IPF patients. Levels of miR-199a-5p were increased selectively in myofibroblasts and putative profibrotic effects of miR-199a-5p were further investigated in cultured lung fibroblasts. MiR-199a-5p expression was induced upon TGFß exposure and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts. CAV1, a critical mediator of pulmonary fibrosis, was established as a bona fide target of miR-199a-5p. Finally, we also found an aberrant expression of miR-199a-5p in mouse models of kidney and liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. We propose miR-199a-5p as a major regulator of fibrosis that represents a potential therapeutic target to treat fibroproliferative diseases.\r\nThis SuperSeries is composed of the SubSeries listed below.
GSE34879 ImmunoHuman AD 38 0 Our understanding of Alzheimer’s disease (AD) pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of AD. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). We reprogrammed primary fibroblasts from two patients with familial AD (both caused by a duplication of APP1, APPDp), two with sporadic AD (sAD1, 2) and two non-demented control individuals (NDCs) into iPSC lines. Neurons from differentiated cultures were FACS-purified and characterized. Purified cultures contained >90% neurons, clustered with fetal brain mRNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APPDp patients and patient sAD2 exhibited significantly higher levels of secreted Aß1-40, phospho-tauThr231 (pTau) and active GSK3ß (aGSK3ß). Neurons from APPDp and sAD2 patients also accumulated large Rab5-positive early endosomes compared to controls. Treatment of purified neurons with ß-secretase inhibitors, but not g-secretase inhibitors, caused significant reductions in pTau and aGSK3ß levels. These results suggest a direct relationship between APP proteolytic processing, but not Aß, in GSK3ß activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial AD samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to AD, even though it can take decades for overt disease to manifest in patients.
GSE35103 ImmunoHuman NormalControl 57 9 The study aims at identifying transcriptional changes induced by in vitro polarization of human cord blood CD4+ cells towards Th17 subtype with combination of IL6, IL1b and TGFb by using timeseries data.\r\nIn this study, we identified gene expression changes characterizing early stages of human Th17 cell differentiation program through genome-wide gene expression profiling. Primary T helper cells isolated from umbilical cord blood were used to construct detailed kinetic patterns of gene expression after initiation of Th17 differentiation with IL1b, IL6 and TGFb. The dataset described provides the starting point for defining the gene regulatory networks and identifying new candidates regulating the Th17 differentiation in human.
GSE35147 ImmunoHuman PulmonaryFibrosis 8 1 This SuperSeries is composed of the SubSeries listed below.
GSE35265 ImmunoHuman Influenza 9 2 Viral infection is commonly associated with virus-driven hijacking of host proteins. We describe a novel mechanism by which influenza virus impacts host cells through the interaction of influenza NS1 protein with the infected cell epigenome. We show that the NS1 protein of influenza A H3N2 targets the transcription elongation PAF1 complex (hPAF1C). We demonstrate that binding of NS1 to hPAF1C results in suppression of hPAF1C-mediated transcriptional elongation.\r\nMore importantly,in the following data sets, we show that hPAF1 plays a crucial role in the antiviral response. Loss of hPAF1C reduces antiviral gene expression and reduces inducible transcription of target genes after stimulation with viral RNA analogue poly(I:C), vesicular stomatitis virus (VSV), exogenous recombinant IFN(beta) and influenza virus (H1N1). This study underscores the importance of hPAF1C in controlling inducible antiviral gene expression.\r\nA549 cells were untreated (no siRNA) or treated with control siRNA-treated and hPAF1 siRNA. Total RNA was isolated with the Qiagen RNeasy mini kit. 200ng of total RNA per sample was used to prepare biotin-labeled RNA using MessageAmp™ Premier RNA Amplification Kit (Applied Biosystems) and hybridized to HumanHT-12 v4 Expression BeadChips (Illumina). Data analysis was performed using the GeneSpring GX11.0 software (Agilent Technologies). These samples were then used for comparisons with stimulated cells (See series 1)
GSE35266 ImmunoHuman Influenza 27 6 Viral infection is commonly associated with virus-driven hijacking of host proteins. We describe a novel mechanism by which influenza virus impacts host cells through the interaction of influenza NS1 protein with the infected cell epigenome. We show that the NS1 protein of influenza A H3N2 targets the transcription elongation PAF1 complex (hPAF1C). We demonstrate that binding of NS1 to hPAF1C results in suppression of hPAF1C-mediated transcriptional elongation.\r\nMore importantly,in the following data sets, we show that hPAF1 plays a crucial role in the antiviral response. Loss of hPAF1C reduces antiviral gene expression and reduces inducible transcription of target genes after stimulation with viral RNA analogue poly(I:C), vesicular stomatitis virus (VSV), exogenous recombinant IFN(beta) and influenza virus (H1N1). This study underscores the importance of hPAF1C in controlling inducible antiviral gene expression.\r\nUntreated (no siRNA), control siRNA-treated and hPAF1 siRNA-treated A549 cells were stimulated with A/Puerto Rico/8/1934 influenza virus (H1N1) or vesicular stomatitis virus (VSV). Total RNA was isolated with the Qiagen RNeasy mini kit. 200ng of total RNA per sample was used to prepare biotin-labeled RNA using MessageAmp™ Premier RNA Amplification Kit (Applied Biosystems) and hybridized to HumanHT-12 v4 Expression BeadChips (Illumina). Data analysis was performed using the GeneSpring GX11.0 software (Agilent Technologies).
GSE35267 ImmunoHuman Influenza 36 9 Viral infection is commonly associated with virus-driven hijacking of host proteins. We describe a novel mechanism by which influenza virus impacts host cells through the interaction of influenza NS1 protein with the infected cell epigenome. We show that the NS1 protein of influenza A H3N2 targets the transcription elongation PAF1 complex (hPAF1C). We demonstrate that binding of NS1 to hPAF1C results in suppression of hPAF1C-mediated transcriptional elongation.\r\nMore importantly,in the following data sets, we show that hPAF1 plays a crucial role in the antiviral response. Loss of hPAF1C reduces antiviral gene expression and reduces inducible transcription of target genes after stimulation with viral RNA analogue poly(I:C), vesicular stomatitis virus (VSV), exogenous recombinant IFN(beta) and influenza virus (H1N1). This study underscores the importance of hPAF1C in controlling inducible antiviral gene expression.\r\nUntreated (no siRNA), control siRNA-treated and hPAF1 siRNA-treated A549 cells were stimulated with PR8/?NS1 influenza virus (MOI 1), IFNß1 (500U/mL) or Poly(I:C) (2ug/mL). Total RNA was isolated with the Qiagen RNeasy mini kit. 200ng of total RNA per sample was used to prepare biotin-labeled RNA using MessageAmp™ Premier RNA Amplification Kit (Applied Biosystems) and hybridized to HumanHT-12 v4 Expression BeadChips (Illumina). Data analysis was performed using the GeneSpring GX11.0 software (Agilent Technologies).
GSE35283 ImmunoHuman 2015Q2 12 3 Highly pathogenic influenza virus inhibit Inflammatory Responses in Monocytes via Activation of the Rar-Related Orphan Receptor Alpha (RORalpha). Low (PR8) and high pathogenic influenza viruses (FPV and H5N1) were used.
GSE35340 ImmunoHuman LungDisease 17 3 Langerhans cell histiocytosis (LCH) is a disease characterized by the accumulation of eponymous CD1a+ Langerin+ Langerhans-cell (LC)-like dendritic cells (DC) of largely unknown origin. Here we have performed comparative transcriptome analysis of highly purified CD207+/CD1a+ Langerhans cell histiocytosis (LCH) cells derived from different locations and disease courses and three major human dendritic cell lineages: epidermal Langerhans cells, myeloid dendritic cells (mDC1) and plasmacytoid dendritic cells (pDC) in order to investigate the relationship between LCH cells and naturally occurring dendritic cells. Data obtained indicate that LCH cells form a distinct DC entity. Furthermore, we have identified transcripts that are uniquely expressed by LCH cells in comparison to LC, mDC1, and pDC, and induce LCH-specific features in human DC.
GSE35571 ImmunoHuman Asthma 131 1 Background\r\nComplex diseases are often difficult to diagnose, treat and study due to the multi-factorial nature of the underlying etiology. Large data sets are now widely available that can be used to define novel, mechanistically distinct disease subtypes (endotypes) in a completely data-driven manner. However, significant challenges exist with regard to how to segregate individuals into suitable subtypes of the disease and understand the distinct biological mechanisms of each when the goal is to maximize the discovery potential of these data sets.\r\nResults\r\nA multi-step decision tree-based method is described for defining endotypes based on gene expression, clinical covariates, and disease indicators using childhood asthma as a case study. We attempted to use alternative approaches such as the Student’s t-test, single data domain clustering and the Modk-prototypes algorithm, which incorporates multiple data domains into a single analysis and none performed as well as the novel multi-step decision tree method. This new method gave the best segregation of asthmatics and non-asthmatics, and it provides easy access to all genes and clinical covariates that distinguish the groups.\r\nConclusions\r\nThe multi-step decision tree method described here will lead to better understanding of complex disease in general by allowing purely data-driven disease endotypes to facilitate the discovery of new mechanisms underlying these diseases. This application should be considered a complement to ongoing efforts to better define and diagnose known endotypes. When coupled with existing methods developed to determine the genetics of gene expression, these methods provide a mechanism for linking genetics and exposomics data and thereby accounting for both major determinants of disease.
GSE35642 ImmunoHuman PD 18 1 The pesticide rotenone, a neurotoxin that inhibits the mitochondrial complex I, and destabilizes microtubules (MT) has been linked to Parkinson disease (PD) etiology and is often used to model this neurodegenerative disease (ND). Many of the mechanisms of action of rotenone are posited mechanisms of neurodegeneration; however, they are not fully understood. Therefore, the study of rotenone-affected functional pathways is pertinent to the understanding of NDs pathogenesis. This report describes the transcriptome analysis of a neuroblastoma (NB) cell line chronically exposed to marginally toxic and moderately toxic doses of rotenone. The results revealed a complex pleiotropic response to rotenone that impacts a variety of cellular events, including cell cycle, DNA damage response, proliferation, differentiation, senescence and cell death, which could lead to survival or neurodegeneration depending on the dose and time of exposure and cell phenotype. The response encompasses an array of physiological pathways, modulated by transcriptional and epigenetic regulatory networks, likely activated by homeostatic alterations. Pathways that incorporate the contribution of MT destabilization to rotenone toxicity are suggested to explain complex I-independent rotenone-induced alterations of metabolism and redox homeostasis. The postulated mechanisms involve the blockage of mitochondrial voltage-dependent anions channels (VDACs) by tubulin, which coupled with other rotenone-induced organelle dysfunctions may underlie many presumed neurodegeneration mechanisms associated with pathophysiological aspects of various NDs including PD, AD and their variant forms. Thus, further investigation of such pathways may help identify novel therapeutic paths for these NDs.
GSE35643 ImmunoHuman Asthma 12 3 Interleukin (IL)-17 plays an important and protective role in host defence and has been demonstrated to orchestrate airway inflammation by cooperating with and inducing proinflammatory cytokines. Mircoarrays were used to identify immediate-early/ primary response IL-17A-dependent gene transcripts in primary human bronchial ASM cells from mild asthmatic and healthy individuals.
GSE35955 ImmunoHuman Arthritis 9 1 In the present study we analyzed the effect of advanced donor age on the transcriptome of human mesenchymal stem cells (hMSC; alternatively named mesenchymal stromal cells) from bone marrow. Human MSC of elderly and middle-aged patients without symptoms of osteoporosis were isolated from femoral heads after total hip arthroplasty.
GSE35956 ImmunoHuman Arthritis 10 1 In the present study we analyzed the effect of primary osteoporosis and advanced donor age on the transcriptome of human mesenchymal stem cells (hMSC; alternatively named mesenchymal stromal cells) from bone marrow. Human MSC of elderly patients suffering from osteoporosis were isolated from femoral heads after low-energy fracture of the femoral neck. Control cells were obtained from bone marrow of femoral heads of middle-aged, non-osteoporotic donors after total hip arthroplasty.
GSE35957 ImmunoHuman Arthritis 10 2 In the present study we analyzed the effect of cellular senescence on the transcriptome of human mesenchymal stem cells (hMSC; alternatively named mesenchymal stromal cells) from bone marrow. Human MSC were isolated from femoral heads of non-osteoporotic donors after total hip arthroplasty.
GSE35958 ImmunoHuman Arthritis 9 1 In the present study we analyzed the effect of primary osteoporosis on the transcriptome of human mesenchymal stem cells (hMSC; alternatively named mesenchymal stromal cells) from human bone marrow. Human MSC of elderly patients suffering from osteoporosis were isolated from femoral heads after low-energy fracture of the femoral neck. Bone marrow of age-matched, non-osteoporotic donors was obtained of femoral heads after total hip arthroplasty.
GSE36177 ImmunoHuman Inflammation 30 2 Several inflammatory diseases respond to TNFa inhibitors, implicating TNFa signaling in the pathogenesis of these conditions. Here, we set out to map the systemic genome-wide transcriptome influenced by TNFa release. We performed an intravenous endotoxin challenge in 16 healthy subjects, half of whom were pretreated with the soluble TNF receptor fusion protein, etanercept. Whole-blood leukocyte total RNA was isolated using the PAXgeneTM tube and PAXgeneTM RNA isolation system (PreAnalytiXTM, Qiagen) as described by the manufacturer. Total RNA yield and purity (260nm:280nm) were determined spectrophotometrically. The integrity of the re-suspended total RNA was determined using the RNA Nano Chip Kit on the Bioanalyzer 2100 and the 2100 Expert software (Agilent). To increase the sensitivity of our gene expression assay, the overload of globin mRNA of whole blood samples was reduced by applying the human GLOBINclear kit (Ambion/Appied Biosystems). Synthesis, amplification and purification of anti-sense RNA was performed using 300 ng of enriched mRNA per sample and the Illumina TotalPrep RNA Amplification Kit (Ambion/Applied Biosystems) following the Illumina Sentrix Array Matrix expression protocol. A total of 750 ng biotinylated cRNA was hybridized onto the HumanHT-12v3 expression BeadChips (Illumina). The BeadChips were scanned according to the protocol described in the Illumina Whole Genome Gene Expression for BeadStation Manual v3.2, Revision A using scanning software BeadScan 3.5.31. The GenomeStudio® Data Analysis Software (Illumina) was used for data collection. Missing values were imputed by using the k-nearest-neighbor algorithm (k=15). The raw scan and imputed data were read using the lumi available through Bioconductor. This was carried out using the R statistical package (version 2.10.1; R Foundation for Statistical Computing, Vienna, Austria). Quality control checks of the raw non-normalized data included visualization of the similarity matrix and hierarchical clustering analysis. Samples for one placebo-treated individual did not pass our quality control checks, and thus were removed from subsequent normalization and analysis. Total RNA isolated from a collection of human tissue-derived cell lines was used as an internal control; this sample also was omitted from subsequent data normalization. Variance stabilizing normalization (Biconductor library vsn) was applied to all other samples. All subsequent analyses were performed on vsn-transformed intensity values.
GSE36221 ImmunoHuman COPD 221 17 Introduction: In the recently completed Dutch GLUCOLD study, treatment of COPD patients with fluticasone ± salmeterol reduced the rate of decline in FEV1. These results indicate that ICS can have therapeutic efficacy in COPD. Aim: To explore the molecular mechanisms by which ICS exert their effects, we performed genome-wide gene expression profiling on bronchial biopsies from COPD patients who participated in the GLUCOLD study. Methods: An Affymetrix Human Gene Array ST version 1.0 was performed in a total of 221 bronchial biopsies that were available from 90 COPD patients at baseline and after 6 and 30 months of therapy. Linear mixed effects modeling was used to analyze treatment-specific changes in gene expression. A validation set was included and pathway analysis was performed with Gene Set Enrichment Analysis (GSEA). Results: The expression of 138 genes significantly decreased after both 6 and 30 months of treatment with fluticasone ± salmeterol versus placebo, whereas the expression of 140 genes increased. A more pronounced treatment-induced change in expression of 51 of these 278 genes was associated with a slower rate of decline in FEV1. Genes that decreased with treatment were involved in pathways related to cell cycle, oxidative phosphorylation, epithelial cell signaling, p53 signaling and T cell signaling. Genes that increased with treatment were involved in pathways related to focal adhesion, gap junction and extracellular matrix deposition. Conclusion: The present study suggests that gene expression in biological pathways of COPD is dynamic with treatment and reflects disease activity. This study opens the gate to targeted and phenotype-driven therapy of COPD.
GSE36287 ImmunoHuman Psoriasis 24 6 The clinical features of psoriasis, characterized by sharply demarcated scaly erythematous plaques, are typically so distinctive that a diagnosis can easily be made on these grounds alone. However, there is great variability in treatment response between individual patients, and this may reflect heterogeneity of inflammatory networks driving the disease. In this study, whole-genome transcriptional profiling was used to characterize inflammatory and cytokine networks in 62 lesional skin samples obtained from patients with stable chronic plaque psoriasis. We were able to stratify lesions according to their inflammatory gene expression signatures, identifying those associated with strong (37% of patients), moderate (39%) and weak inflammatory infiltrates (24%). Additionally, we identified differences in cytokine signatures with heightened cytokine-response patterns in one sub-group of lesions (IL-13-strong; 50%) and attenuation of these patterns in a second sub-group (IL-13-weak; 50%). These sub-groups correlated with the composition of the inflammatory infiltrate, but were only weakly associated with increased risk allele frequency at some psoriasis susceptibility loci (e.g., REL, TRAF3IP2 and NOS2). Our findings highlight variable points in the inflammatory and cytokine networks known to drive chronic plaque psoriasis. Such heterogeneous aspects may shape clinical course and treatment responses, and can provide avenues for development of personalized treatments.\r\nWe used Affymetrix microarrays to evaluate genome-wide expression in primary human keratinocytes exposed to cytokines. Cytokine activity signatures were used to interpret the shifts in gene expression that occur in psoriasis plaques relative to normal uninvolved skin.
GSE3629 ImmunoHuman IBD 121 1 Samples were taken from either surgically resected specimens or during surveillance colonoscopic examination. The expression profiles were determined using Affymetrix Human Genome U133 Plus 2.0 arrays. Comparison between the sample groups allow to identify a set of discriminating genes that can be used for molecular markers for predicting development of cancer and/or dysplasia in ulcerative colitis, and to characterize potential diagnostic markers in UC-associated neoplasm.
GSE36381 ImmunoHuman nomodel 17 0 Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding an NF-kB activator within skin epidermis, account for PSORS2. Here we describe fifteen additional rare, missense variants in CARD14, their distribution in seven psoriasis cohorts (>6,000 cases and >4,000 controls), and their effects on NF-kB activation and the transcriptome of keratinocytes. There was an excess of rare variants within CARD14 in cases versus controls (burden test p-value = 0.0015). Some variants were only seen in a single case and included putative pathogenic mutations (c.424G>A [p.Glu142Lys], c.425A>G [p.Glu142Gly]) and the generalized pustular psoriasis mutation, c.413A>C (p.Glu138Ala), that lie within the coiled-coil domain of CARD14. The c.349G>A (p.Gly117Ser) familial psoriasis mutation was present at a frequency of 0.0005 in cases of European ancestry. CARD14 variants led to a range of NF-kB activities, with putative pathogenic variants leading to levels >2.5-fold higher than wildtype CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with TNF-a to achieve significant increases in NF-kB levels. Transcriptome profiling of wildtype and variant CARD14 transfectants in keratinocytes differentiated likely pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD14 polymorphisms were also genotyped and meta-analysis revealed association of psoriasis with rs11652075 (c.2458C>T/p.Arg820Trp; p-value = 2.1x10-6). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw*0602 (PSORS1). These studies contribute to our understanding of the genetic basis of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease.
GSE36387 ImmunoHuman Psoriasis 16 2 Psoriasis is a common, immune-mediated, genetic disorder of the skin associated with arthritis in approximately 30% of cases. Previously, we localized PSORS2 (psoriasis susceptibility locus 2) to chromosome 17q25.3-qter following a genome-wide linkage scan in a family of European origin with multiple cases of psoriasis and psoriatic arthritis. Linkage to PSORS2 was also observed in a multiply affected psoriasis family from Taiwan. With genomic capture and DNA sequencing, we identified unique gain-of-function mutations in caspase recruitment domain family, member 14 (CARD14) that segregated with psoriasis. The mutations, c.349G>A (p.Gly117Ser) and c.349+5G>A respectively, altered splicing between exons 3 and 4 of CARD14. A de novo mutation in CARD14, c.413A>C [p.Glu138Ala], was detected in a child with sporadic, early-onset, generalized pustular psoriasis. CARD14 activates nuclear factor kappa B (NF-kB), and the p.Gly117Ser and p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes compared to wildtype CARD14. These included chemokine (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8). CARD14 is localized mainly in the basal and suprabasal layers of healthy skin epidermis, while in lesional psoriatic skin it is reduced in the basal layer and more diffusely upregulated in the suprabasal layers of the lesional epidermis. We propose that, following a triggering event that can include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration that is the hallmark of psoriasis.
GSE36553 ImmunoHuman 2015Q2 40 6 MicroRNAs (miRNAs) repress the expression levels of genes by binding to mRNA transcripts, acting as master regulators of cellular processes. Differential expression of miRNAs has been linked to viral-associated diseases involving members of the hepacivirus, herpesvirus, and retrovirus families. In contrast, limited biological and molecular information has been reported on the potential role of cellular miRNAs in the lifecycle of influenza A viruses (infA). In this study, we hypothesize that elucidating the miRNA expression signatures induced by low-pathogenic swine-origin influenza A virus (S-OIV) pandemic H1N1 (2009) and highly pathogenic avian-origin (A-OIV) H7N7 (2003) infections could reveal temporal and strain-specific miRNA fingerprints during the viral lifecycle, shedding important insights into the potential role of cellular miRNAs in host-infA interactions. Using a microfluidic microarray platform, we profiled cellular miRNA expression in human A549 cells infected with S- and A-OIVs at multiple time-points during the viral lifecycle, including global gene expression profiling during S-OIV infection. Using target prediction and pathway enrichment analyses, we identified the key cellular pathways associated with the differentially expressed miRNAs and predicted mRNA targets during infA infection, including immune system, cell proliferation, apoptosis, cell cycle, and DNA replication and repair. By identifying the specific and dynamic molecular phenotypic changes (microRNAome) triggered by S- and A-OIV infection in human cells, we provide experimental evidence demonstrating a series of temporal- and strain-specific host molecular responses involving different combinatorial contributions of multiple cellular miRNAs. Our results also identify novel potential exosomal miRNA biomarkers associated with pandemic S-OIV and deadly A-OIV-host infection.
GSE36700 ImmunoHuman Arthritis 25 4 Rheumatoid arthritis (RA) is an inflammatory joint disorder that results in progressive joint damage when insufficiently treated. In order to prevent joint destruction and functional disability in RA, early diagnosis and initiation of appropriate treatment with Disease-Modifying Antirheumatic Drugs (DMARDs) is needed. However, in daily clinical practice, patients may initially display symptoms of arthritis that do not fulfil the classification criteria for a definite diagnosis of RA, or any other joint disease, a situation called “Undifferentiated Arthritis” (UA). Out of the patients with UA, 30 to 50% usually develop RA, and early identification of these remains a challenge.\r\n\r\nAt the present time, although several risk factors associated with the development of RA have been identified (6-9), a model that reliably predicts the probability of evolution of UA into RA in individual patients is lacking. In order to better identify early RA patients, an American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) collaboration recently developed new classification criteria. Although these criteria are more sensitive, the risk of over-diagnosis is an important issue to consider, especially in very early disease. In this context, the present study explores the feasibility of a molecular diagnosis of arthritis, based on the identification of disease-specific transcriptomic profiles in synovial biopsies from patients with arthritis according to the underlying condition.\r\nIn a previous study, we performed global analyses of gene expression in synovial biopsies from patients with RA, Systemic Lupus Erythematosus (SLE) and Osteoarthritis (OA), using high-density oligonucleotide spotted microarrays. We found that the gene expression profiles are strikingly different according to the underlying condition. Thus, the majority of the genes up-regulated in SLE are type I Interferon-inducible genes, as compared with the up-regulation genes involved in T cell and B cell activation in RA, and in extracellular matrix homeostasis in OA. Based on these results, similar analyses were performed in synovial biopsies from patients with seronegative arthritis (SA) and microcrystalline arthritis (MIC), in order to identify disease-specific molecular signatures.
GSE36807 ImmunoHuman IBD 35 2 Gene expression patterns of Crohn's disease (CD) and ulcerative colitis (UC) colonic specimens were analyzed using whole-genome microarrays. Healthy control samples were included in order to detect gene expression changes associated with CD or UC. CD and UC samples were also compared in order to identify the molecular mechanisms that distinguish both fenotypes of inflammatory bowel disease.
GSE36941 ImmunoHuman SLE 20 2 Systemic lupus erythematosus (SLE) is a T and B cell-dependent autoimmune disease characterized by the appearance of autoantibodies, a global regulatory T cells (Tregs) depletion and an increase in Th17 cells. Recent studies have shown the multifaceted immunomodulatory effects of vitamin D, notably the expansion of Tregs and the decrease of Th1 and Th17 cells. A significant correlation between higher disease activity and lower serum 25-hydroxyvitamin D levels was also shown.\r\nThis preliminary study suggests the beneficial role of vitamin D in SLE patients and needs to be confirmed in randomized controlled trials.
GSE36980 ImmunoHuman AD 79 3 To identify molecular pathological alterations in AD brains, we performed interspecies comparative microarray analyses using RNAs prepared from postmortem human brain tissues donated for the Hisayama study and hippocampal RNAs from the triple-transgenic mouse model of AD (3xTg-AD)\r\nThree-way ANOVA of microarray data from frontal cortex, temporal cortex and hippocampus with presence/absence of AD and vascular dementia, and sex, as factors revealed that the gene expression profile is most significantly altered in the hippocampi of AD brains. Comparative analyses of the brains of AD patients and a mouse model of AD showed that genes involved in non-insulin dependent DM and obesity were significantly altered in both, as were genes related to psychiatric disorders and Alzheimer’s disease.
GSE37107 ImmunoHuman Arthritis 14 1 B cell depletion therapy is efficacious in RA patients failing on TNF blocking agents. However, approximately 40-50% of the rituximab-treated RA patients have a poor response. We investigated wheter baseline gene expression levels can discriminate between clinical nonresponders and responders to rituximab
GSE37147 ImmunoHuman COPD 269 2 RNA was isolated from bronchial brushings obtained from current and former smokers with and without COPD. mRNA expression was profiled using Affymetrix Human Gene 1.0 ST Arrays.
GSE37157 ImmunoHuman Asthma 28 5 Analysis of gene-expression profiles by microarrays can be very useful to characterize new potential candidate genes, key regulatory networks, and to define phenotypes or molecular signatures to improve the diagnosis or classification of the disease. We have used this approach in the study of one of the major causes of allergic diseases in Mediterranean countries, the olive pollen response, in order to find differential molecular markers among five clinical groups, Non-allergic, Asymptomatic, Allergic but not to olive pollen, Non-treated, olive pollen allergic patients and Olive pollen allergic patients (under specific-immunotherapy). The results of gene-expression by principal components analysis (PCA) clearly showed five clusters of samples that correlated with the five clinical groups. Analysis of differential gene-expression by multiple testing, and functional analysis by KEGG and Gene-Ontology revealed differential genes and pathways among the 5 clinical groups.
GSE37263 ImmunoHuman AD 16 1 We investigated genome-wide gene alterations in the temporal cortex of a well-characterized cohort of Alzheimer’s disease (AD) patients using Affymetrix exon arrays.
GSE37283 ImmunoHuman IBD 20 2 Background and Aims: Individuals with ulcerative colitis (UC) are at increased risk for colorectal cancer, although underlying mechanisms are incompletely understood. We sought to identify a potential gene expression signature in non-dysplastic distal mucosa that as a “genetic field effect” could be a marker for remote neoplastic lesions.\r\nResults: 468 genes were significantly up-regulated and 541 genes were significantly down-regulated >2-fold in UC patients with neoplasia compared to UC patients without neoplasia. Nine genes (ACSL1, BIRC3, CLC, CREM, ELTD1, FGG, S100A9, THBD, and TPD52L1) were progressively and significantly up-regulated from controls to quiescent non-dysplastic UC to UC with neoplasia. Immunostaining of proteins revealed increases in tissue expression of S100A9 and REG1 in UC-associated cancer and in non-dysplastic tissue from UC patients harboring remote neoplasia, compared to UC patients without dysplasia and normal controls.\r\nConclusions: Gene expression changes occur as a field effect in UC patients without active inflammation who harbor a remote dysplastic lesion. Further characterization of these genes and proteins might elucidate pathways of carcinogenesis in IBD and lead to the development of more accurate, less invasive markers of dysplasia in those at increased risk.
GSE37356 ImmunoHuman SLE 72 4 To examine mononuclear cell gene expression profiles in patients with and without SLE and subsets with and without atherosclerosis
GSE37455 ImmunoHuman SLE 41 1 Expression data from human with hypertensive nephropathy (HT)\r\nWe used microarrays to analyze the transcriptome of microdissected renal biopsies from patients with HT
GSE37460 ImmunoHuman SLE 69 2 Expression data from human with IgA nephropathy (IgAN) and hypertensive nephropathy (HT)\r\nWe used microarrays to analyze the transcriptome of microdissected renal biopsies from patients with IgAN and HT
GSE37573 ImmunoHuman SLE 104 3 In this report we applied standard and original methods of analysis of gene expression microarray data to delineate differences in the molecular pathways impacted by stimulation of Epstein-Barr virus (EBV) transformed B cells derived from patients with systemic lupus erythematosus (SLE) and normal unrelated controls. In order to understand the dynamics and interconnections the B cell molecular pathways, the system was perturbed with a biologically relevant signal, co-crosslinking of the B cell antigen receptor (BCR) and Fc?R2b and global gene expression changes were assessed at various timepoints post-stimulation. Both traditional analysis of differential gene expression and analysis of the dynamics of gene expression variations were performed. Combining these two methods in an analysis process we call Pathway Dysregulation Analysis allows us to establish model networks of functional gene expression important for B cell signaling responses and elucidate gene expression regulatory interconnections disrupted in B cells from individuals with lupus. Through this technique, we found two main groups of gene associations changed significantly with the disease phenotype, which included genes with established controlling function of the B cell activation, and genes involved in apoptosis initiation or prevention.
GSE37584 ImmunoHuman MultipleSclerosis 14 3 Genome-wide association studies in multiple sclerosis (MS) identified a polymorphism (rs6897932) located in the coding region of the alpha chain of the cytokine receptor interleukin 7 receptor (IL7R) as a component that increases susceptibility to develop the disease. This single nucleotide polymorphism (SNP) affects the splicing of the primary transcript leading to genotype-defined transcript ratios encoding either a full length membrane spanning form or a soluble receptor chain. Genotyping at the IL7R locus reveals that the region can be described by four haplotypes. Interestingly, only one out of three haplotypes harbouring the associated SNP is positively associated with MS whereas the other two do not show association. The minor allele containing haplotype shows a reduced susceptibility to develop MS. We hypothesized that additional functional or phenotypic differences exist between individuals homozygous for haplotypes shown to have either positive, negative, or neutral effect, on susceptibility to develop MS. Gene expression profiles of CD4+ T cells from MS individuals before and after stimulation with IL7 were recorded. Haplotype-specific gene signatures were found indicating small alterations in IL7/IL7R signal processing/sensitivity through JAK/STAT and p38/MAPK14. We can not exclude that the obtained signatures result from differences within the CD4+ T cell compartment that, in fact, should be seen as a consequence of systemic haplotype-specific processing of homeostatic and proliferation signals transmitted through IL7/IL7R.
GSE37693 ImmunoHuman COPD 8 1 Primary culture airway epithelial cells, grown under physiologic air-liquid interface conditions, with, or without IL-13 in order to study the effects of this cytokine on mucous cell metaplasia, an important feature of asthma and COPD.
GSE37750 ImmunoHuman MultipleSclerosis 26 2 Multiple Sclerosis (MS) is an immune-mediated chronic inflammatory disease affecting the central nervous system. The cause of MS is not known and the mechanism of IFN-beta, a disease-modifying treatment (DMT) approved for MS, is not well-understood. Oligonucleotide microarrays were used to study gene expression in plasmacytoid denditic cells (pDCs) which are antigen-presenting cells implicated in MS pathogenesis.\r\nWe analyzed gene expression in pDCs of healthy controls, untreated and IFN-beta treated MS patients. We were able to identify 60 genes which were abnormally expressed in untreated MS patients and were corrected after treatment with IFN-beta.
GSE37768 ImmunoHuman COPD 38 2 Chronic obstructive pulmonary disease (COPD) is a progressive and irreversible chronic inflammatory lung disease. The abnormal inflammatory response of the lung, mainly to cigarette smoke, causes multiple cellular and structural changes affecting all of its compartments, which leads to disease progression. The molecular mechanisms underlying these pathological changes are still not fully understood\r\nThe aim of this study was to identify genes and molecular pathways potentially involved in the pathogenesis of COPD
GSE37783 ImmunoHuman MultipleSclerosis 12 1 Natalizumab is a recombinant monoclonal antibody raised against integrin alpha-4 (CD49d). It is approved for the treatment of patients with multiple sclerosis (MS), a chronic inflammatory autoimmune disease of the CNS. Natalizumab blocks leukocyte extravasation across the blood-brain barrier by inhibiting the molecular interaction between integrin alpha-4/beta-1 heterodimers expressed on leukocytes and VCAM-1 on inflammatory-activated CNS endothelium. Here we investigated whether binding of this adhesion-blocking antibody to T lymphocytes modulated their phenotype by direct induction of intracellular signaling events. Natalizumab induced a mild upregulation of IL-2, IFN-gamma and IL-17 expression in activated primary human CD4+ T cells propagated ex vivo from healthy donors, consistent with a pro-inflammatory costimulatory effect on lymphokine expression. Overall, the relative effect of natalizumab was more pronounced in less than in fully activated T cells. Along with this, natalizumab binding triggered rapid MAPK/ERK phosphorylation. Furthermore, it decreased CD49d surface expression on effector cells within a few hours. Sustained CD49d downregulation could be attributed to integrin internalization and degradation. Importantly, also CD4+ T cells from some MS patients receiving their very first dose of natalizumab produced more IL-2, IFN-gamma and IL-17 already 24 h after infusion. Together these data indicate that in addition to its adhesion-blocking mode of action, natalizumab possesses mild direct signaling capacities, which may support a pro-inflammatory phenotype of peripheral blood T lymphocytes. This might explain why a rebound of disease activity is observed in some MS patients after natalizumab cessation.
GSE38267 ImmunoHuman SystemicSclerosis 64 2 Genes dysregulated in cystic fibrosis (CF) and primary pulmonary arterial hypertension (PAH) at a late stage of pulmonary failure are still largely unknown. Blood samples taken in the frame of the French cohort of lung transplantation COLT offers the opportunity to identify in blood specific gene signatures of each disease and a common gene signature for both pathologies. A microarray analysis was performed with homogeneous groups of CF patients (n=23), PAH (n=13) patients and healthy volunteers (n=28). Blood was collected in a PAXgene® tube to maintain RNA integrity. Total extracted RNA were processed on 60K whole-genome microarrays (Agilent Technologies). Microarrays were analyzed by bioinformatics (GOminer and Ingenuity Pathway Analysis). Three major biological signatures were discovered including (1) genes specifically over-expressed in pPAH and mainly involved in inflammation, vascular remodeling and cell proliferation, (2) genes specifically over-expressed in CF involved in innate immune response and oxidative stress response, and (3) genes under-expressed in both diseases, including genes involved in transcriptional machinery, apoptosis and cell proliferation.
GSE38351 ImmunoHuman SLE 74 6 Many cytokines are involved in the pathogenesis of autoimmune diseases and are recognized as relevant therapeutic targets to attenuate inflammation, such as TNFa in RA and IFNa/? in SLE. To relate the transcriptional imprinting of cytokines in a cell type-specific and disease-specific manner, we generated gene-expression profiles from peripheral monocytes of SLE and RA patients and compared them to in vitro-generated signatures induced by TNFa, IFNa2a and IFN?. Monocytes from SLE and RA patients revealed disease-specific gene-expression profiles. In vitro-generated signatures induced by IFNa2a and IFN? showed similar profiles that only partially overlapped with those induced by TNFa. Comparisons between disease-specific and in vitro-generated signatures identified cytokine-regulated genes in SLE and RA with qualitative and quantitative differences. The IFN-responses in SLE and RA were found to be regulated in a STAT1-dependent and STAT1-independent manner, respectively. Similarly, genes recognized as TNFa-regulated were clearly distinguishable between RA and SLE patients. While the activity of SLE monocytes was mainly driven by IFN, the activity from RA monocytes showed a dominance of TNFa that was characterized by STAT1 down-regulation. The responses to specific cytokines were revealed to be disease-dependent and reflected the interplay of cytokines within various inflammatory milieus. This study has demonstrated that monocytes from RA and SLE patients exhibit disease-specific gene-expression profiles, which can be molecularly dissected when compared to in vitro-generated cytokine signatures. The results suggest that an assessment of cytokine-response status in monocytes may be helpful for improvement of diagnosis and selection of the best cytokine target for therapeutic intervention.
GSE38530 ImmunoHuman PulmonaryFibrosis 20 3 Idiopathic pulmonary fibrosis (IPF) is an untreatable fibrotic lung disease characterized by fibroblast proliferation and epithelial mesenchymal transition.miRNA let-7d and mir30b were found to be signifcantly down regulated in IPF. Compared to control we over expressed these miRNAs in Human Fetal Lung Fibroblast cell line
GSE38713 ImmunoHuman IBD 43 3 Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with preiods of active disease followed by remission.\r\nWe performed a whole-genome transcriptional analysis of colonic biopsies from patients with histologically active and inactive UC, as well as non-inflammatory controls.
GSE38849 ImmunoHuman Arthritis 11 1 Objective. Follistatin-like protein 1 (FSTL-1) is a secreted glycoprotein that is over-expressed in certain inflammatory diseases. Our objective in this study was to correlate FSTL-1 levels with measures of clinical disease activity in systemic juvenile idiopathic arthritis (sJIA), including macrophage activation syndrome (MAS).\r\nMethods. FSTL-1 serum levels were measured by ELISA in 28 patients with sJIA, including 7 patients who developed MAS, as well as in 30 normal controls. Levels were correlated with erythrocyte sedimentation rate (ESR), ferritin and sIL-2Ra expression. Differential gene expression based on FSTL-1 levels was analyzed in peripheral blood mononuclear cells (PBMCs).\r\nResults. FSTL-1 serum levels were elevated at time of presentation (pre-treatment) of sJIA (mean 200.7 ng/ml) and decreased to normal (mean 133.7 ng/ml) over 24 months (p<0.01). FSTL-1 levels were markedly elevated during acute MAS (mean 279.8 ng/ml) and decreased to normal (mean 120.3 ng/ml) following treatment (p<0.001). FSTL-1 levels correlated with serum markers of inflammation, including sIL-2Ra and ferritin, in patients with MAS. PBMCs from patients with FSTL-1 levels >200 ng/ml showed an increase in expression of genes related to innate immunity and erythropoiesis, and decrease in NK cell function. Patients with the highest FSTL-1 levels at disease onset (>300 ng/ml) ultimately required cyclosporine treatment.\r\nConclusion. In patients with sJIA, serum FSTL-1 is a biomarker for MAS and FSTL-1 levels at presentation may predict subsequent disease course. Patients with FSTL-1 levels >200 ng/ml had altered gene expression patterns suggestive of subclinical MAS and may represent a subgroup of sJIA with more severe disease.
GSE38934 ImmunoHuman COPD 6 1 Combined pulmonary fibrosis and emphysema (CPFE) is characterized by upper-lobe emphysema combined with lower-lobe fibrosis and a high prevalence of pulmonary hypertension. The aim of this study was to measure and analyze gene expression profiles in the lungs of CPFE patients.\r\nThe results showed that the expression profiles of the fibrotic and emphysematous lesions were remarkably different in terms of function. Genes related to immune system, structural constituents of cytoskeleton, and cellular adhesion were overexpressed in fibrotic lesions, while genes associated with cellular fraction, cell membrane structures, vascular growth and biology, second-messenger-mediated signaling, and lung development (all processes that contribute to the destruction and repair of cells, vessels, and lung) were overexpressed in emphysematous lesions.\r\nThe differences in gene expression were detected in fibrotic and emphysematous lesions in CPFE patients. We propose that the development of coexisted fibrotic and emphysematous lesions in CPFE is implemented by these different patterns of gene expressions.
GSE38974 ImmunoHuman COPD 32 3 70 miRNAs and 2667 mRNAs were differentially expressed between lung tissue from subjects with COPD and smokers without COPD. miRNA and mRNA expression profiles enriched for biological pathways that may be relevant to the pathogenesis of COPD including the transforming growth factor b, Wnt and focal adhesion pathways. miR-223 and miR-1274a were the most affected miRNAs in subjects with COPD compared with smokers without obstruction. miR-15b was increased in COPD samples compared with smokers without obstruction and localised to both areas of emphysema and fibrosis. miR-15b was differentially expressed within GOLD classes of COPD. Expression of SMAD7, which was validated as a target for miR-15b, was decreased in bronchial epithelial cells in COPD.
GSE39088 ImmunoHuman SLE 142 28 We performed a phase I/II, randomized, double-blind, placebo-controlled dose-escalation study to examine the safety, immunogenicity, and biological effects of active immunization with interferon alpha-Kinoid (IFN-K) in systemic lupus erythematosus (SLE) patients. Women 18-50 years of age with mild to moderate SLE were immunized with three (n=10) or four doses (n=9) of 30, 60, 120, 240 microgram IFN-K or saline.\r\nAnti-IFNalpha antibodies were detected in all IFN-K-immunized patients. Transcriptomic analysis separated patients at baseline into type I IFN signature-positive and -negative groups. IFN-K induced higher anti-IFNalpha titers in signature-positive than in signature-negative patients and, in signature-positive patients, reduced the expression of IFN-induced genes. The decrease in IFN score correlated with the anti-IFNalpha antibody titers, and with baseline IFN score.
GSE39340 ImmunoHuman Arthritis 22 2 Gene expression microarray was applied to discover novel rheumatoid arthritis (RA)-specific gene expressions by comparing the expression profiles of synovial membranes from patients with RA, osteoarthritis (OA) and ankylosing spondylitis (AS). We performed a gene expression microarray analysis of RA synovial membranes and simultaneously compared the expression profile with the profiles of AS and OA synovial membranes.
GSE39420 ImmunoHuman AD 21 2 Alzheimer’s disease (AD) is the most common neurodegenerative dementia. Around 10% of cases present an age of onset before 65 years-old, which in turn can be divided in monogenic or familial AD (FAD) and sporadic early-onset AD (EOAD). Mutations in PSEN1, PSEN2 and APP genes have been linked with FAD. The aim of our study was to describe the brain whole-genome RNA expression profile of the posterior cingulate area in EOAD and FAD caused by PSEN1 mutations (FAD-PSEN1). 14 patients (7 EOAD and 7 FAD-PSEN1) and 7 neurologically healthy controls were selected and samples were hybridized in a Human Gene 1.1 microarray from Affymetrix. When comparing controls with EOAD and controls with FAD-PSEN1, we found 3183 and 3351 differentially expressed genes (DEG) respectively (FDR corrected p<0.05). However, any DEG was found in the comparison of the two groups of patients. Microarrays were validated through quantitative-PCR of 17 DEG. In silico analysis of the DEG revealed an alteration in biological pathways related to calcium-signaling, axon guidance and long-term potentiation (LTP), among others, in both groups of patients. These pathways are mainly related with cell signalling cascades, synaptic plasticity and learning and memory processes. In conclusion, the altered biological final pathways in EOAD and FAD-PSEN1 are highly coincident. Also, the findings are in line with those previously reported for late-onset AD (LOAD, onset >65 years-old), which implies that the consequences of the disease at the molecular level are similar in the final stages of the disease.
GSE39594 ImmunoHuman NormalControl 21 4 We used microarrays to detail the global gene transcription underlying T cells activation during the first 24 hours after stimulation.
GSE39999 ImmunoHuman IBD 6 2 Nematode derived substances are known to down regulate host immune responses in order to survive in the human host. Brugia malayi is a parasitic nematode responsible for long lasting and disabling infection known as lymphatic filariasis in humans. The therapeutic benefit of a controlled parasitic nematode infection on the course of inflammatory bowel disease (IBD) has been demonstrated in both animal and human models. However the inability of individual purified nematode proteins to recreate this beneficial effect has limited the application of component immunotherapy to human disease. This experiment addresses the hypothesis that the genes regulated by IL8 and recombinant Brugia malayi AsnRS (rBmAsnRS) are different even though it is known that both molecules interact with IL-8 receptors. Furthermore, we theorize that the signal transduction pathways activated by IL-8 and rBmAsnRS are different because it is known that the extracellular G protein loops utilized by IL-8 and rBmAsnRS to activate IL8 receptors, are different. These results obtained with a single recombinant nematode protein, rBmAsnRS, share immunological features with those observed in a whole nematode infection and include desirable features for treatment of idiopathic inflammatory diseases, such as IBD.
GSE40012 ImmunoHuman 2015Q2 190 4 Introduction: Diagnosis of severe influenza pneumonia remains challenging because of the lack of correlation between presence of influenza virus and patient’s clinical status. We conducted gene expression profiling in the whole blood of critically ill patients to identify a gene signature that would allow clinicians to distinguish influenza infection from other causes of severe respiratory failure (e.g. bacterial pneumonia, non-infective systemic inflammatory response syndrome). Methods: Whole blood samples were collected from critically ill individuals and assayed on Illumina HT-12 gene expression beadarrays. Differentially expressed genes were determined by linear mixed model analysis and over-represented biological pathways determined using GeneGo MetaCore. Results: The gene expression profile of H1N1 influenza A pneumonia was distinctly different from bacterial pneumonia and systemic inflammatory response syndrome. The influenza gene expression profile is characterized by up-regulation of genes from cell cycle regulation, apoptosis and DNA-damage response pathways. In contrast, no distinctive gene-expression signature was found in patients with bacterial pneumonia or systemic inflammatory response syndrome. The gene expression profile of influenza infection persisted through five days of follow-up. Furthermore, in patients with primary H1N1 influenza A infection who subsequently developed bacterial co-infection, the influenza gene-expression signature remained unaltered, despite the presence of a super-imposed bacterial infection. Conclusions: The whole blood expression profiling data indicates that the host response to influenza pneumonia is distinctly different from that caused by bacterial pathogens. This information may speed up identification of the cause of infection in patients presenting with severe respiratory failure, allowing appropriate patient care to be undertaken more rapidly.
GSE40033 ImmunoHuman Psoriasis 14 2 Object: To study the difference of gene expression pattern of bone marrow mesenchymal stem cells (BMMSCs) between psoriatic patients, normal adults and aborted fetuses, and then to explore the influence of bone marrow mesenchymal stem cells to immune system. Methods: Bone marrow mononuclear cells (BMMNC) of 7 psoriatic patients, 4 healthy volunteers and 3 aborted fetuses were isolated and the BMMSCs were cultured using the adherent method. Gene expression of 14 samples was detected by gene microarray and the different expressed genes were analysised by SAM software. Results: 654 differentially expressed genes (66 up regulated, 588 down regulated) were detected between the psoriatic patients and normal adults, which were enriched in immune response, chemotaxis and cell adhesion etc. 2020 differentially expressed genes (888 up regulated, 1132 down regulated) were detected between the aborted fetuses and normal adults. These genes were enriched in cell cycle, cell division, immune response and MHC class II antigen etc. Conclusion: The gene expression pattern such as immune response, chemotaxis was aberrant in psoriatic BMMNCs, which was consistent with aborted fetuses in some immune related genes.
GSE40240 ImmunoHuman Asthma 28 5 To determine differential gene expression in peripheral blood of asthmatic individuals undergoing allergen inhalation challenge between early responders (ERs) and dual responders (DRs) following allergen inhalation challenge
GSE40263 ImmunoHuman Psoriasis 30 7 Oxidative damage contributes significantly to the pathogenesis of psoriasis. We recently developed antioxidative peptides (UPF peptides) activating the endogenous glutathione system (GSH). In the present study, we analyzed gene expression profiles in the samples of psoriasis patients to find if these peptides could reduce oxidative damage during psoriasis.\r\nPeripheral blood mononuclear cells (PBMCs) from patients with psoriasis and from healthy controls were collected and cultivated. Cultured PBMCs were incubated with two different UPF peptides for 12 hours. Gene expression analysis was performed with Affymetrix Human Gene 1.0 ST arrays and with quantitative real-time PCR. Gene expression profile in the PBMCs of patients with psoriasis indicated significant up-regulation of the immune response pathway. Treatment with UPF peptides normalized the gene expression pattern in psoriasis samples. Therefore, treatment with antioxidative drugs have potential anti-psoriatic activity.
GSE40281 ImmunoHuman Influenza 9 2 Highly pathogenic avian influenza viruses (HPAIV) induce severe inflammation in poultry and men. There is still an ongoing threat that these viruses may acquire the capability to freely spread as novel pandemic virus strains that may cause major morbidity and mortality. One characteristic of HPAIV infections is the induction of a cytokine burst that strongly contributes to viral pathogenicity. It has been suggested, that this cytokine overexpression is an intrinsic feature of infected cells and involves hyperinduction of p38 mitogen activated protein kinase (MAPK). Here we investigate the role of MAPK p38 signaling in the antiviral response against HPAIV in mice as well as in endothelial cells, the latter a primary source for cytokines during systemic infections.\r\nGlobal gene expression profiling of HPAIV infected endothelial cells in the presence of the MAP kinase p38-specific inhibitor SB202190 revealed, that inhibition of MAPK p38 leads to reduced expression of interferon (IFN) and other cytokines after A/Thailand/1(KAN-1)/2004 (H5N1) and A/FPV/Bratislava/79 (H7N7) infection. Furthermore, the expression of interferon stimulated genes (ISGs) after treatment with IFN or conditioned media from HPAIV infected cells was decreased when the target cells were preincubated with SB202190. Finally, promoter analysis confirmed a direct impact of p38 MAPK on the IFN-enhanceosome and ISG-promoter activity. In vivo inhibition of MAP kinase p38 greatly diminishes virus induced cytokine expression concomitant with reduced viral titers, thereby protecting mice from lethal infection.\r\nThese observations show, that MAPK p38 acts on two levels of the antiviral IFN response: Initially the kinase regulates IFN induction and at a later stage MAPK p38 controls IFN signaling and thereby expression of IFN-stimulated genes. Thus, inhibition of MAP kinase p38 may be an antiviral strategy that significantly protects mice from lethal influenza via suppression of overshooting cytokine expression.
GSE40364 ImmunoHuman COPD 116 2 Motivation: Identification of eQTL, the genetic loci that contribute to heritable variation in gene expression, can be obstructed by factors that produce variation in expression profiles if these factors are unmeasured or hidden from direct analysis.\r\nMethods: We have developed a method for Hidden Expression Factor analysis (HEFT) that identifies individual and pleiotropic effects of eQTL in the presence of hidden factors. The HEFT model simultaneously accounts for the effects of genotypes while learning hidden factors, where we make use of the complete likelihood of a unified multivariate regression and factor analysis model to derive a ridge estimator for combined factor learning and detection of eQTL. HEFT requires no pre-estimation of hidden factor effects, no iterative model selection, it provides p-values, and is extremely fast, requiring just a few hours to complete an eQTL analysis of thousands of expression variables when analyzing hundreds of thousands of SNPs on a standard 8 core 2.6G desktop.\r\nResults: By analyzing simulated data, we demonstrate that HEFT can correct for an unknown number of hidden factors and outperforms related hidden factor methods for eQTL analysis, where the improved performance is particularly evident in the detection of eQTL with multivariate effects. To demonstrate a real-world application, we applied HEFT to identify eQTL affecting gene expression in human lung tissue for a study that included presumptive hidden factors. The analysis identified a number of eQTL with direct relevance to lung disease that could not be found without a hidden factor analysis, including cis-eQTL for GTF2H1 and MTRR, genes that have been independently associated with lung cancer.
GSE40438 ImmunoHuman ALS 8 1 A consistent clinical feature of amyotrophic lateral sclerosis (ALS) is the sparing of eye movements. Pathological studies have confirmed that there is relative sparing of the cranial motor nuclei of the oculomotor, trochlear and abducens nerves, although pathological changes resembling those seen in anterior horn cells are present to a lesser degree. The aim of the present study is to combine LCM and microarray analysis to study the differences between motor neurons that are selectively resistant (oculomotor neurons) and those that are vulnerable (lumbar spinal motor neurons) to the disease process in amyotrophic lateral sclerosis.
GSE40484 ImmunoHuman ChronicInflammation 22 4 Transcriptome analysis of five population of Antigen Presenting Cells: inflammatory macrophages, Inflammatory dendritic cells, Cd14+CD16- monocytes, CD14 dim Cd16+ monocytes and BDCA1+ Dendritic cells.
GSE40711 ImmunoHuman 2015Q2 12 3 Background. The pathogenesis of influenza A virus subtype H5N1 (hearafter, "H5N1") infection in humans is not completely understood, although hypercytokinemia is thought to play a role. We previously reported that most H5N1 viruses induce high cytokine responses in human macrophages, whereas some H5N1 viruses induce only a low level of cytokine production similar to that induced by seasonal viruses.\r\nMethods. To identify the viral molecular determinants for cytokine induction of H5N1 viruses in human macrophages, we generated a series of reassortant viruses between the high cytokine inducer A/Vietnam/UT3028II/03 clone 2 (VN3028IIcl2) and the low inducer A/Indonesia/UT3006/05 (IDN3006), and evaluated cytokine expression in human macrophages.\r\nResults. Viruses possessing the acidic polymerase (PA) gene of VN3028IIcl2 exhibited high levels of hypercytokinemia-related cytokine expression in human macrophages, compared with IDN3006, but showed no substantial differences in viral growth in these cells. Further, the PA gene of VN3028IIcl2 conferred enhanced virulence in mice.\r\nConclusions. These results demonstrate that the PA gene of VN3028IIcl2 affects cytokine production in human macrophages and virulence in mice. These findings provide new insights into the cytokine-mediated pathogenesis of H5N1 infection in humans.
GSE40839 ImmunoHuman SystemicSclerosis 21 2 Pulmonary fibrosis develops as a consequence of environmentally induced lung injury and/or an inherent disease susceptibility causing fibroblast activation, proliferation and extracellular matrix deposition.\r\nThe study was undertaken to characterise global gene expression in pulmonary fibroblasts to better understand the mechanisms underlying the fibrotic fibroblast phenotype.
GSE40885 ImmunoHuman Asthma 14 1 Rationale: Lipopolysaccharide (LPS) is ubiquitous in the environment. Inhalation of LPS has been implicated in the pathogenesis and/or severity of several lung diseases, including pneumonia, chronic obstructive pulmonary disease and asthma. Alveolar macrophages are the main resident leukocytes exposed to inhaled antigens. Objectives: To obtain insight into which innate immune pathways become activated within human alveolar macrophages upon exposure to LPS in vivo.
GSE40887 ImmunoHuman 2015Q2 8 1 Reveal differentially regulated genes and cellular pathways within allergic and non-allergic asthmatic children compared to healthy controls
GSE40888 ImmunoHuman 2015Q2 105 8 Reveal differentially regulated genes and cellular pathways within allergic and non-allergic asthmatic children compared to healthy controls
GSE40889 ImmunoHuman 2015Q2 113 9 This SuperSeries is composed of the SubSeries listed below.
GSE4097 ImmunoHuman AD 6 1 The amyloid precursor protein (APP) plays a central role in the pathogenesis of Alzheimer’s disease (AD). Processing of APP by ß- and ?-secretase activities results in the production of ß-amyloid (Aß), the main constituent of Alzheimer plaques, but also in the generation of the APP intracellular domain (AICD). Recently, it has been demonstrated that AICD has transactivation potential, however, the targets of AICD dependent gene regulation and hence the physiological role of AICD remain largely unknown. In this work we analysed transcriptome changes during AICD dependent gene regulation using a human neural cell culture system inducible for expression of AICD, its co-activator Fe65, or the combination of both. Induction of AICD was associated with increased expression of genes with known function in the organization and dynamics of the actin cytoskeleton as well as genes involved in the regulation of apoptosis.
GSE41067 ImmunoHuman 2015Q2 24 7 Genome-wide gene expression patterns were measured in human monocyte-derived dendritic cells (DCs) infected in vitro with seasonal H1N1 influenza A/New Caledonia/20/1999. To provide a mechanistic explanation for the timing of gene expression changes over the first 12 hours post-infection, we developed a statistically rigorous enrichment approach integrating genome-wide expression kinetics and time-dependent promoter analysis. Our approach, TI me-Dependent Activity Linker (TIDAL), generates a regulatory network that connects transcription factors associated with each temporal phase of the response into a coherent linked cascade. TIDAL infers 12 transcription factors and 32 regulatory connections that drive the antiviral response to influenza. To demonstrate the generality of this approach, TIDAL was also used to generate a network for the DC response to measles infection.
GSE41649 ImmunoHuman Asthma 8 1 Allergic asthma is a complex trait. Several approaches have been used to identify biomarkers involved in this disease. This study aimed at demonstrating the relevance and validity of microarrays in the definition of allergic asthma expression pattern. The authors compared the transcript expressions of bronchial biopsy of 2 different microarray experiments done 2 years apart, both including nonallergic healthy and allergic asthmatic subjects (n = 4 in each experiment). U95Av2 and U133A GeneChips detected respectively 89 and 40 differentially expressed genes. Fifty-five percent of the U133A genes were previously identified with the U95Av2 arrays. The immune signaling molecules and the proteolytic enzymes were the most preserved categories between the 2 experiments, because 3/4 of the genes identified by the U133A were also significant in the U95Av2 study for both categories. These results demonstrate the relevance of microarray experiments using bronchial tissues in allergic asthma. The comparison of these GeneChip studies suggests that earlier microarray results are as relevant as actual ones to target new genes of interest, particularly in function categories linked to the studied disease. Moreover, it demonstrates that microarrays are a valuable technology to target novel allergic asthma pathways as well as biomarkers.
GSE41662 ImmunoHuman Psoriasis 48 1 To explore the psoriasis phenotype and pathways involved in psoriasis, we characterized gene expression in lesional and non-lesional skin from psoriasis patients.
GSE41663 ImmunoHuman Psoriasis 81 5 cDNA and cRNA hybridization technologies have different, probe-specific sensitivities. We used samples from an etanercept trial (GSE11903) to explore in a real-life setting the uniqueness of each platform.
GSE41745 ImmunoHuman 2015Q2 6 1 The transcriptomic profiling of psoriasis has led to an increased understanding of disease pathogenesis. Although microarray technologies have been instrumental in this regard, it is clear that these tools detect an incomplete set of DEGs. RNA-seq can be used to supplement these prior technologies. Here, the use of RNAseq methods substantially increased the number of psoriasis-related DEGs. Furthermore, DEGs that were uniquely identified by RNA-seq, but not in other published microarray studies, further supported the role of IL-17 and tumor necrosis factor-a synergy in psoriasis. Examination of one of these factors at the protein level confirmed that RNA-seq is a powerful tool that can be used to identify molecular factors present in psoriasis lesions, and may be useful in the identification of therapeutic targets that to our knowledge have not been reported previously. Further studies are in progress to determine the biological significance of DEGs uniquely discovered by RNA-seq.
GSE4183 ImmunoHuman IBD 53 3 Background and Aims: Gene expression analysis of colon biopsies using high-density oligonucleotide microarray can contribute to the understanding of local pathophysiological alterations and to functional classification of precancerous adenoma, different stage colorectal carcinomas (CRC) and inflammatory bowel diseases (IBD).\r\nResults: Significant overexpression of collagen IV?1, lipocalin-2, caveolin-1, calumenin genes, and significant dowregulation of aquaporin-8, amnionless homolog, prostaglandin D2 receptor genes were detected in CRC patients compared to normal. Adenoma samples were characterized by upregulated CD44 antigen, met proto-oncogene and downregulated chemokine ligand-12, ADAM-like decysin-1 and ATP-binding casette A8 discriminatory genes. In IBD samples significantly increased lipocalin-2, interferon induced transmembrane protein 1 and 3 mRNA levels, decreased zinc finger protein 91 and transient receptor potential cation channel M6 mRNA levels were found. Ulcerative colitis and Crohn’s disease can be distinguished according to the top five genes: cyclin-G2; tripartite motif-containing-31; TNFR shedding aminopeptidase regulator-1; C-type lectin superfamily member-14 and AMICA. 88.3-97.8% of the cases was correctly classified according to discriminatory genes.\r\nConclusions: Our whole genomic microarray analysis of biopsy samples provides discriminative signatures, and an insight into pathophysiological background of colonic diseases. The results afford a data warehouse which can be further mined for in-depth pathway analyses.
GSE41831 ImmunoHuman Arthritis 78 4 Remission has become both the gold standard for clinical care and the end point for clinical trials for children with juvenile idiopathic arthritis (JIA). Using gene expression microarrays, we found that when remission induced by methotrexate (MTX) or MTX plus a TNF inhibitor (etanercept, Et) (MTX+Et) was compared with healthy controls, there were notable differences in gene expression patterns, demonstrating that remission is not a restoration of immunologic normalcy. Differences were detected in PBMC as well as in granulocytes.
GSE41861 ImmunoHuman Asthma 138 2 Molecular profiling studies in asthma cohorts have identified a Th2-driven asthma subtype, characterized by elevated lower airway expression of POSTN, CLCA1 and SERPINB2. To assess upper airway gene expression as a potential biomarker for lower airway Th2 inflammation, we assayed upper airway (nasal) and lower airway (bronchial) epithelial gene expression, serum total IgE, blood eosinophils and serum periostin in a cohort of 54 allergic asthmatics and 30 matched healthy controls. 23 of 51 asthmatics in our cohort were classified as ‘Th2 high’ based on lower airway Th2 gene signature expression. Consistent with this classification, ‘Th2 high’ subjects displayed elevated total IgE and blood eosinophil levels relative to ‘Th2 low’ subjects. Upper airway Th2 signature expression was significantly correlated with lower airway Th2 signature expression (r=0.44), with similar strength of association as serum total IgE and blood eosinophils, known biomarkers of Th2 inflammation. In an unbiased genome-wide scan, we identified 8 upper airway genes more strongly correlated with lower airway Th2 gene signature expression (r=0.58), including Eotaxin-3 (CCL26), Galectin-10 (CLC) and Cathepsin-C (CTSC). Asthmatics classified as ‘Th2 high’ using this 8-gene signature show similar serum total IgE and blood eosinophil levels as ‘Th2 high’ asthmatics classified using lower airway Th2 gene signature expression. We have identified an 8-gene upper airway signature correlated with lower airway Th2 inflammation, which may be used as a diagnostic biomarker for Th2-driven asthma.
GSE41862 ImmunoHuman Asthma 116 1 Gene expression profiling was performed on nasal scrape samples obtained from asthmatics and matched healthy controls, to identify markers associated with various asthma subtypes.
GSE41863 ImmunoHuman Asthma 56 1 Gene expression profiling was performed on sputum samples obtained from asthmatics and matched healthy controls, to identify markers associated with various asthma subtypes.
GSE41890 ImmunoHuman 2015Q2 68 2 Whole-genome expression of peripheral blood leukocytes was measured in 22 patients and 24 controls using the Human Gene 1.0 ST array by Affymetrix
GSE41905 ImmunoHuman Psoriasis 6 1 MiR-31 is one of the most highly overexpressed miRNAs in psoriasis skin; however, its biological role in the disease has not been studied. Here we show that miR-31 is markedly overexpressed in psoriasis keratinocytes. To study the biological role of miR-31 in keratinocytes, we transfected miR-31 hairpin inhibitor (anti-miR-31) into primary human keratinocytes to inhibit endogenous miR-31. We performed a global transcriptome analysis of keratinocytes upon suppression of endogenous miR-31 using Affymetrix arrays.
GSE41999 ImmunoHuman NormalControl 12 2 Recently, hypoxia via the transcription factor HIF-1a has been implicated to play an important role for the fate of the adaptive immune response by regulatory T cells (Treg) and T helper 17 cells (TH17) in the mouse model. However, the reports on the effect of HIF-1a are conflicting and so far no functional data in the human system are available. Therefore, we analyzed the effect of hypoxia and HIF-1a on Treg and TH17 in the human system. FACS, western blot and reporter assays clearly demonstrated that hypoxia does not up-regulate the level of HIF-1a in CD4+ T cells (THC) and microarray analysis revealed no change of the transcriptome comparing normoxia vs. hypoxia. Furthermore, we could show that HIF-1a is almost exclusively regulated via NF-kB and NFAT, whereas hydroxylation and subsequent degradation of HIF-1a had little to no effect. In addition, we showed that HIF-1a is essential for nTreg mediated suppression and for IL-17A secretion of TH17, but not for TH17 lineage commitment measured by ROR?t expression. In conclusion, our results demonstrated that THC have a distinct regulation of HIF-1a protein levels, which was absolutely essential for Treg and TH17 function.
GSE42026 ImmunoHuman 2015Q2 92 3 In order to understand the immunopathogenesis of severe influenza H1N1/09, we compared the whole blood RNA transcriptome of children hospitalised with H1N1/09 infection with that of children hospitalised with RSV or bacterial infection\r\nBlood was collected into PAX gene tubes (PreAnalytiX). Total RNA integrity was assessed using an Agilent 2100 Bioanalyzer (Agilent, Palo Alto, CA). Labeled cRNA was hybridized to Illumina Human HT-12 v3 Beadchips.
GSE42057 ImmunoHuman COPD 136 4 Expression data were generated on 136 subjects from the COPDGene® study using Affymetrix microarrays. Multiple linear regression with adjustment for covariates (gender, age, body mass index, family history, smoking status, pack years) was used to identify candidate genes and Ingenuity Pathway Analysis was used to identify candidate pathways.\r\nCandidate genes identified included those that play a role in the immune system, inflammatory responses, and sphingolipid metabolism. Many of our final candidate genes also show an association with related disease phenotypes such as emphysema, gas trapping, and 6-minute walk distance.
GSE42296 ImmunoHuman Arthritis 78 4 We used microarrays to identify markers predicting responder status in infliximab treatment in 19 rheumatoid arthritis and 20 Crohn's disease patients at week 0 and week 2 of treatment.
GSE42305 ImmunoHuman Psoriasis 15 4 Our group recently described a population of antigen presenting cells that appear to be critical in psoriasis pathogenesis, termed inflammatory myeloid dendritic cells (CD11c+ BDCA1-). Triggering receptor expressed on myeloid cells type-1 (TREM-1) signaling was a major canonical pathway in the published transcriptome of these cells. TREM-1 is a member of the immunoglobulin superfamily, active through the DAP12 signaling pathway, with an unknown ligand. Activation through TREM-1 induces inflammatory cytokines including IL-8, MCP/CCL2 and TNF. We now show that TREM-1 was expressed in the skin of healthy and psoriatic patients, and there was increased soluble TREM-1 in the circulation of psoriasis patients. In psoriasis lesions, TREM-1 was co-localized with dendritic cells as well as CD31+ endothelial cells. TREM-1 expression was reduced with successful NB-UVB, etanercept and anti-IL-17 treatments. An in vitro model of PGN-activated monocytes as inflammatory myeloid DCs was developed to study TREM-1 blockade, and treatment with a TREM-1 blocking chimera decreased allogeneic Th17 activation, as well as IL-17 production. Furthermore, TREM-1 blockade of ex vivo psoriatic dendritic cells in an alloMLR also showed a decrease in IL-17. Together, these data suggest that the TREM-1 signaling pathway offers a novel therapeutic target to prevent the effects of inflammatory myeloid DCs in psoriasis.
GSE42519 ImmunoHuman nomodel 34 0 We used microarray to create a normal cell landscape for the myeloid arm of the hematopoietic system.
GSE42569 ImmunoHuman NormalControl 4 1 Th17 cells are believed to be a critical cell population for driving autoimmune diseases. However, environmental factors that are directly related to the development of Th17 cells are largely unknown.\r\nHigh-salt (NaCl) concentrations enhance Th17 differentiation of human naive CD4+ T cells in vitro. The aim of the study was to analyse the changes in gene expression induced by high-salt conditions during Th17 differentiation.
GSE42606 ImmunoHuman InfectiousDisease 299 8 Candida albicans is the most common human fungal pathogen causing mucosal and systemic infections, but human anti-fungal immunity remains poorly defined. Expression profiling of Candida-stimulated human peripheral blood mononuclear cells (PBMCs) provides new insights into Candida-specific host defense mechanisms in humans.
GSE42632 ImmunoHuman Psoriasis 12 1 Several studies have suggested that MSCs have pleiotropic immuno-modulatory effects, including inhibition of T cell proliferation, suppression of NK cells proliferation, modulation of cytokine production, and inhibition of dendritic cell (DC) maturation etc. But the exactly mechanism are still largely unclear. We proposed to investigate the mRNA expression profile of psoriatic MSCs.
GSE42763 ImmunoHuman 2015Q2 37 4 The purpose of this study was to analyze the transcriptional effects induced by glatiramer acetate treatment (GA; Copaxone, 20 mg injected subcutaneously once daily) in blood monocytes of patients with relapsing-remitting form of multiple sclerosis (MS). By using Affymetrix DNA microarrays, we obtained genome-wide expression profiles of monocytes from 8 MS patients within the first two months of GA administration.
GSE42911 ImmunoHuman IBD 10 1 Genome wide expression profiling of ulcerative colitis, and normal colon mucosa samples. The GeneChip PrimeView Human Gene Expression Array was used to obtain expresion profiles across colon mucosa samples. Samples came from 5 ulcerative colitis affected, and 5 normal individuals.
GSE4302 ImmunoHuman Asthma 118 2 We collected airway epithelial brushings for microarray analysis from 42 asthmatics and two control groups – 28 healthy subjects and 16 smokers. A subgroup of 32 asthmatics completed a randomized placebo-controlled trial of fluticasone propionate in which collection of brushings was repeated after 1 week of treatment.
GSE43191 ImmunoHuman Arthritis 23 0 The aim of this study is to identify, for the first time, the genome-wide DNA methylation profiles of human articular chondrocytes from OA and healtly cartilage samples.\r\nA subsequent validation of methylation profiles were performed in an idependent cohort of OA samples with Affymetrix Hugene 1.1 st array\r\nThis represents the gene expression component of the study only
GSE43326 ImmunoHuman AD 6 1 Oligomeric forms of amyloid-beta peptide (Abeta) are presumed to play a pivotal role in the pathogenesis of Alzheimer’s disease (AD). However, it is still unclear how Abeta oligomers contribute to AD pathogenesis in patient neural cells. We generated induced pluripotent stem cells (iPSCs) from a familial AD patient and differentiated them into neural cells. Abeta oligomers were accumulated in neural cells of AD bearing amyloid precursor protein (APP)-E693delta mutation.\r\nTo uncover Abeta oligomers in AD(APP-E693delta) neural cells, we analyzed gene expression profiles of control and the AD neural cells
GSE43397 ImmunoHuman Asthma 50 1 Systemic inflammation is reported to be associated with neutrophilic airway inflammation in asthma, this study aimed to examine the molecular mechanisms of the neutrophilia that is associated with systemic inflammation, and hypothesized that asthma patients with systemic inflammation have a group of genes that are differentially expressed and are assciated with airway inflammation.
GSE43409 ImmunoHuman NormalControl 11 3 ROR gamma t+ innate lymphoid cells (ILC) are crucial players of innate immune responses and represent a major source of IL-22, which has an important role in mucosal homeostasis. The signals required by ROR gamma t+ ILC to express IL-22 and other cytokines, including TNF, have only partially been elucidated. Here we show that ROR gamma t+ ILC can directly sense the environment by the engagement of the activating receptor NKp44. NKp44 triggering in ROR gamma t+ ILC selectively activates a coordinated pro-inflammatory program, including TNF, while cytokine stimulation induces preferentially IL-22 expression. However, combined engagement of NKp44 and cytokine receptors results in a strong synergistic effect. These data support the concept that NKp44+ ROR gamma t+ ILC can be activated without cytokines and are able to switch between IL-22 or TNF production, depending on the triggering stimulus.
GSE43515 ImmunoHuman Asthma 54 15 Multi-walled carbon nanotubes (MWCNT) cause lung fibrosis in rodents and exacerbate airway fibrosis in the mouse ovalbumin model of allergic asthma. Interleukin 13 (IL-13) is a key cytokine secreted by T helper type 2 (Th2) cells. IL-13 is up-regulated in human asthma and animal models that activate pro-fibrotic and pro-proliferative cell signaling cascades in human lung fibroblasts (HLF). This study tested the hypothesis that IL-13 alters the gene expression profile of HLF exposed to MWCNT. Carbon black nanoparticles (CBNP) were also compared to MWCNT as they are relatively inert nanoparticles that do not cause fibrosis. Confluent, quiescent cultures of HLF were treated with 10 ng/ml IL-13 or serum-free defined medium (vehicle) for 24 hours prior to treatment with 10 µg/cm2 MWCNT or CBNP. At 4, 24, or 48 hours following nanoparticle exposure, total RNA was isolated and gene expression was measured using the Affymetrix Human Genome U133A2.0 Array. The data were analyzed using the JMP Genomics statistical platform. IL-13 and MWCNT each caused changes in the expression of distinct gene subsets over the time-course investigated. The combination of IL-13 and MWCNT resulted in a gene expression profile that was distinct from patterns induced or suppressed by either IL-13 or MWCNT alone. CBNP caused changes in gene expression that were distinct from IL-13 or MWCNT. Interestingly, the combination of IL-13 and MWCNT increased the expression of IL-17A and increased collagen (Col1A1), while MWCNT alone increased interferon-inducible protein-27 (IFI27), suggesting that Th2 microenvironment containing IL-13 shifts MWCNT-induced gene expression from a Th1 to a Th17 gene expression profile. These data provide insight into the mechanisms by which MWCNT alter the biology of fibroblasts during normal and allergic inflammatory conditions.
GSE43553 ImmunoHuman Arthritis 100 4 To analyse gene expression patterns and to define a specific gene expression signature in patients with the severe end of the spectrum of cryopyrin-associated periodic syndromes (CAPS). The molecular consequences of interleukin 1 inhibition were examined by comparing gene expression patterns in 16 CAPS patients before and after treatment with anakinra.\r\nMany DEG include transcripts related to the regulation of innate and adaptive immune responses, oxidative stress, cell death, cell adhesion and motility. A set of gene expression-based models comprising the CAPS-specific gene expression signature correctly classified all 17 samples from an independent dataset. This classifier also correctly identified 15 of 16 post-anakinra CAPS samples despite the fact that these CAPS patients were in clinical remission. We identified a gene expression signature that clearly distinguished CAPS patients from controls. A number of DEG were in common with other systemic inflammatory diseases such as systemic onset juvenile idiopathic arthritis. The CAPS-specific gene expression classifiers also suggest incomplete suppression of inflammation at low doses of anakinra.
GSE43591 ImmunoHuman 2015Q2 20 1 MicroRNAs are small noncoding RNA molecules that are involved in the control of gene expression. To investigate the role of microRNA in multiple sclerosis (MS), we performed global microarray analyses of mRNA and microRNA in peripheral blood T-cells from relapsing-remitting MS patients and controls. We identified 2,452 regulated genes and 21 regulated microRNA that differed between MS patients and controls. By Kolmogorov-Smirnov test, 20 of 21 regulated microRNA were shown to affect the expression of their target genes, many of which are involved in the immune system. LIGHT (TNFSF14) was a microRNA target gene significantly decreased in MS. The down-regulation of mir-494 and predicted mRNA-target LIGHT was verified by real-time PCR and we could demonstrate decreased serum levels of LIGHT in MS. Thus, regulated microRNA were significantly associated with both gene and protein expression of a molecule in immunological pathways. These findings indicate that microRNA may be important regulatory molecules in T-cells in MS.
GSE43696 ImmunoHuman Asthma 108 2 Bronchial Epithelial Cells were isolated processed as described (Chu et al., 2002 and Zhao et al., 2011). The objective of the study was to identify differentially expressed genes between normal control (NC), mild-moderate asthmatic (MMA) and severe asthmatic (SA) patients.
GSE43923 ImmunoHuman Arthritis 6 1 Pigment Epithelium-Derived Factor (PEDF) has recently been identified as a factor that is significantly upregulated in late-stage osteoarthritic cartilage in which chondrocytes are confronted with terminal differentiation and cell death. Since PEDF is known to induce cell death of endothelial cells, it may also be responsible for terminal differentiation and cell death in cartilage.
GSE43939 ImmunoHuman COPD 149 2 Study Smoking and COPD are associated with decreased mucociliary clearance and healthy smokers have shorter cilia in the large airway than nonsmokers. Intraflagellar transport (IFT) is the process by which cilia are produced and maintained. We assessed expression of IFT-related genes in smokers and nonsmokers and evaluated cilia length in the large and small airway of nonsmokers, healthy smokers, and smokers with COPD.\r\nMethods Airway epithelium was obtained via bronchoscopic brushing. Affymetrix microarrays were used to evaluate IFT gene expression in 2 independent data sets from large and small airway. Cilia length was assessed by measuring 100 cilia (10 cilia on each of 10 cells) per subject.\r\nResults All 40 IFT genes were expressed in the human large and small airway epithelium. In the large airway, 10 IFT genes were down-regulated and 1 up-regulated in smokers. In the small airway, 11 genes were down-regulated and 3 up-regulated in smokers. A set of 8 IFT genes was down-regulated in both data sets. In the large and small airway epithelium, cilia were significantly shorter in healthy smokers than nonsmokers, and significantly shorter in COPD smokers than in both healthy smokers and nonsmokers.\r\nAnswer to the Question These results support the concept that loss of cilia length contributes to defective mucociliary clearance in COPD, and that smoking-induced changes in expression of IFT genes may be one mechanism of abnormally short cilia in smokers. Strategies to normalize cilia length may be an important avenue for novel COPD therapies.
GSE44037 ImmunoHuman Asthma 34 4 The link between upper and lower airways in patients with both asthma and allergic rhinitis is still poorly understood. As the biological complexity of these disorders can be captured by gene expression profiling we hypothesized that the clinical expression of rhinitis and/or asthma is related to differential gene expression between upper and lower airways epithelium.\r\nWe used micro array to profile gene expression of primary nasal and bronchial epithelial cells from the same individuals and examining the impact of allergic rhinitis with and without concomitant allergic asthma on expression profiles.
GSE44201 ImmunoHuman NormalControl 75 8 Analysis of human peripheral blood 48 hours after irradiation ex vivo with graded doses of gamma rays. Results have been used in building and testing classifiers to predict exposure dose for use in radiological triage, and also provide insight into immune cell responses. Results were compared with those from earlier times and from patients exposed in vivo.
GSE44248 ImmunoHuman Asthma 96 6 Glucocorticoids (GCs) are key mediators of stress response and are widely used as pharmacological agents to treat immune diseases, such as asthma and inflammatory bowel disease, and certain types of cancer. GCs act mainly by activating the GC receptor (GR), which interacts with other transcription factors to regulate gene expression. Here, we combined different functional genomics approaches to gain molecular insights into the mechanisms of action of GC. By profiling the transcriptional response to GC over time in 4 Yoruba (YRI) and 4 Tuscans (TSI) lymphoblastoid cell lines (LCLs), we suggest that the transcriptional response to GC is variable not only in time, but also in direction (positive or negative) depending on the presence of specific interacting TFs. Accordingly, when we performed ChIP-seq for GR and NF-kB in two YRI LCLs treated with GC or with vehicle control, we observed that features of GR binding sites differ for up- and down-regulated genes. Finally, we show that eQTLs that affect expression patterns only in the presence of GC are 1.9-fold more likely to occur in GR binding sites, compared to eQTLs that affect expression only in its absence. Our results indicate that genetic variation at GR and interacting transcription factors binding sites influences variability in gene expression, and attest to the power of combining different functional genomic approaches.
GSE44719 ImmunoHuman Influenza 77 14 While dendritic cells (DCs) are known to play a major role in the process of vaccination, the mechanisms by which vaccines induce protective immunity in humans remain elusive. Herein, we used gene microarrays to characterize the transcriptional programs induced over time in human monocyte-derived DCs (moDCs) in vitro in response to influenza H1N1 Brisbane, Salmonella enterica and Staphylococcus aureus. We built a data-driven modular analytical framework focused on 204 pathogen-induced gene clusters. The expression of these modules was analyzed in response to 16 well-defined ligands, targeting TLRs, cytoplasmic PAMP receptors and cytokine receptors. This multi-dimensional framework covers the major biological functions of APC, including the IFN response, inflammation, DC maturation, T cell activation, antigen processing, cell motility and histone regulation. This framework was used to characterize the response of monocytes and moDCs to 14 commercially available vaccines. These vaccines displayed quantitatively and qualitatively distinct modular signatures in monocytes and DCs, in particular Fluzone and Pneumovax, highlighting the functional and phenotypic differences between APC subsets. This modular framework allows the application of systems immunology approaches to study early transcriptional changes in human APC subsets in response to pathogens and vaccines, which might guide the development of improved vaccines.
GSE44720 ImmunoHuman Influenza 120 30 While dendritic cells (DCs) are known to play a major role in the process of vaccination, the mechanisms by which vaccines induce protective immunity in humans remain elusive. Herein, we used gene microarrays to characterize the transcriptional programs induced over time in human monocyte-derived DCs (moDCs) in vitro in response to influenza H1N1 Brisbane, Salmonella enterica and Staphylococcus aureus. We built a data-driven modular analytical framework focused on 204 pathogen-induced gene clusters. The expression of these modules was analyzed in response to 16 well-defined ligands, targeting TLRs, cytoplasmic PAMP receptors and cytokine receptors. This multi-dimensional framework covers the major biological functions of APC, including the IFN response, inflammation, DC maturation, T cell activation, antigen processing, cell motility and histone regulation. This framework was used to characterize the response of monocytes and moDCs to 14 commercially available vaccines. These vaccines displayed quantitatively and qualitatively distinct modular signatures in monocytes and DCs, in particular Fluzone and Pneumovax, highlighting the functional and phenotypic differences between APC subsets. This modular framework allows the application of systems immunology approaches to study early transcriptional changes in human APC subsets in response to pathogens and vaccines, which might guide the development of improved vaccines.
GSE44723 ImmunoHuman PulmonaryFibrosis 14 2 Genomic profiling of RNA from cultured human fibroblasts of donor samples in the 10-14th passage was carried out to determine expression changes in the fibroblasts of individual with different degrees of pulmonary fibrosis. Donors consisted of individuals with rapid progressing pulmonary fibrosis, slow progressing pulmonary fibrosis, or no fibrosis.
GSE4498 ImmunoHuman COPD 22 1 Modification of Gene Expression of the Small Airway Epithelium in Response to Cigarette Smoking\r\nThe earliest morphologic evidence of changes in the airways associated with chronic cigarette smoking is in the small airways. To help understand how smoking modifies small airway structure and function, we developed a strategy using fiberoptic bronchoscopy and brushing to sample the human small airway (10th-12th order) bronchial epithelium to assess gene expression (HG-133 Plus 2.0 array) in phenotypically normal smokers (n=10, 33 ± 7 pack-yr) compared to matched non-smokers (n=12). Even though the smokers were phenotypically normal, analysis of the small airway epithelium of the smokers compared to the non-smokers demonstrated up- and -down-regulation of genes in multiple categories relevant to the pathogenesis of chronic obstructive lung disease (COPD), including genes coding for cytokines/innate immunity, apoptosis, mucin, response to oxidants and xenobiotics, and general cellular processes. In the context that COPD starts in the small airways, these gene expression changes in the small airway epithelium in phenotypically normal smokers are candidates for the development of therapeutic strategies to prevent the onset of COPD.
GSE45111 ImmunoHuman Asthma 47 2 This study identifies differentially expression genes in the sputum of people with eosinophilic, neutrophilic and paucigranulocytic asthma. A selection of markers identified using this microarray were further validated using qPCR on a wider sample set.
GSE45233 ImmunoHuman Arthritis 12 2 In this study, we have tested the variation in gene expression signatures in human injured meniscus with age and degree of chondrosis in the knee. We found several genes that were differentially regulated with each of these factors and they represent important biological pathways in osteoarthritis research.
GSE45251 ImmunoHuman Asthma 16 1 Background: Tissue remodeling induced by airway inflammation is a main trigger of pathogenesis in various chronic lung diseases like asthma, COPD, IPF, and pulmonary hypertension. The role of human airway smooth muscle cells (HASMCs) in this context is unclear. Hypothesis: HASMCs participate in linking inflammation with remodeling. Methods: The inflammatory responses of ex vivo-cultivated HASMCs to TNFa were investigated by whole-genome-microarray analyses. Diferrential regulation of genes associated with airway inflammation and remodeling were verified by qRT-PCR and ELISA. Results: TNFa induced the expression of 18 cytokines/chemokines and five tissue remodeling genes involved in (severe/corticosteroid-insensitive) asthma, COPD, IPF and/or pulmonary hypertension. Conclusion: HASMCs participate in the interaction of inflammation and tissue remodeling. HASMCs might be considered as targets in therapies of chronic inflammatory lung diseases with regard to attenuating inflammation-induced remodeling processes leading to the development of emphysema or fibrosis.
GSE45291 ImmunoHuman Arthritis 805 3 Whole blood expression was profiled in Rheumatoid Arthiritis and SLE (Systemic LUPUS Erythomatosus) patients.
GSE45422 ImmunoHuman SLE 6 1 The present gene expression array study of fluvastatin effects on monocytes from SLE patients show that fluvastatin has a global anti-inflammatory effect on monocytes, which includes attenuated expression of several proinflammatory cytokines, and regulated expression of molecules mediating lipoprotein signaling and cholesterol metabolism, as well as atherosclerosis and inflammatory signaling.
GSE45468 ImmunoHuman 2015Q2 216 4 To further explore predictors and targets of response to infliximab, differential gene expression was examined at baseline and after 6 and 24 hours and 2 weeks after the first infusion of infliximab in TRD patients who were infliximab responders versus nonresponders, and compared to placebo-treated patients.\r\nAll subjects were administered either infliximab (5mg/kg, n=30) or placebo (n=30) through an indwelling catheter at the Emory Division of Digestive Diseases at 3 separate time points (baseline, 2 weeks and 6 weeks). Infliximab infusion dosing protocol and scheduling were matched to the standard intravenous induction routine for the treatment of inflammatory bowel disease.
GSE45535 ImmunoHuman nomodel 12 0 Objective: Production of pathogenic autoantibodies by self-reactive plasma cells (PC) is a hallmark of autoimmune diseases. Investigating the prevalence of PC in autoimmune disease and their relationship with known pathogenic pathways may increase our understanding of the role of PC in disease progression and treatment response. Methods: We developed a sensitive gene expression based method to overcome the challenges of measuring PC using flow cytometry. Whole genome microarray analysis of sorted cellular fractions identified a panel of genes, IGHA, IGJ, IGKC, IGKV, and TNFRSF17, expressed predominantly in PC. The sensitivity of the PC signature score created from the combined expression levels of these genes was assessed through ex vivo experiments with sorted cells. This PC gene expression signature was used for monitoring changes in PC levels following anti-CD19 therapy; evaluating the relationship between PC and other autoimmune disease-related genes; and estimating PC levels in affected blood and tissue from multiple autoimmune diseases. Results: The PC signature was highly sensitive and capable of detecting as few as 300 PCs. The PC signature was reduced over 90% in scleroderma patients following anti-CD19 treatment and this reduction was highly correlated (r = 0.77) with inhibition of collagen gene expression. Evaluation of multiple autoimmune diseases revealed 30-35% of lupus, rheumatoid arthritis, and scleroderma patients with increased PC levels. Conclusion: This newly developed PC signature provides a robust and accurate method to measure PC levels in the clinic. Our results highlight subsets of patients across multiple autoimmune diseases that may benefit from PC depleting therapy.
GSE45536 ImmunoHuman SystemicSclerosis 123 5 Objective: Production of pathogenic autoantibodies by self-reactive plasma cells (PC) is a hallmark of autoimmune diseases. Investigating the prevalence of PC in autoimmune disease and their relationship with known pathogenic pathways may increase our understanding of the role of PC in disease progression and treatment response. Methods: We developed a sensitive gene expression based method to overcome the challenges of measuring PC using flow cytometry. Whole genome microarray analysis of sorted cellular fractions identified a panel of genes, IGHA, IGJ, IGKC, IGKV, and TNFRSF17, expressed predominantly in PC. The sensitivity of the PC signature score created from the combined expression levels of these genes was assessed through ex vivo experiments with sorted cells. This PC gene expression signature was used for monitoring changes in PC levels following anti-CD19 therapy; evaluating the relationship between PC and other autoimmune disease-related genes; and estimating PC levels in affected blood and tissue from multiple autoimmune diseases. Results: The PC signature was highly sensitive and capable of detecting as few as 300 PCs. The PC signature was reduced over 90% in scleroderma patients following anti-CD19 treatment and this reduction was highly correlated (r = 0.77) with inhibition of collagen gene expression. Evaluation of multiple autoimmune diseases revealed 30-35% of lupus, rheumatoid arthritis, and scleroderma patients with increased PC levels. Conclusion: This newly developed PC signature provides a robust and accurate method to measure PC levels in the clinic. Our results highlight subsets of patients across multiple autoimmune diseases that may benefit from PC depleting therapy.
GSE45665 ImmunoHuman Arthritis 8 1 Decoy receptor 3 (DcR3), a member of the tumor necrosis factor receptor (TNFR) superfamily, competitively binds and inhibits members of the TNF family, including Fas ligand (FasL), LIGHT, and TL1A. DcR3 was recently reported not only to act as a decoy receptor for these TNFRs but also to play a role as a ligand for the pathogenesis of RA.\r\nWe hypothesized that DcR3 regulates the gene expression in RA-FLS. We used to search for genes in which expression in RA-FLS is regulated by the ligation of DcR3.
GSE45686 ImmunoHuman PulmonaryFibrosis 40 5 Analysis of gene expression of lung fibroblasts seeded onto decellularized extracellular matrix (ECM). Experiment had 2x2 design where fibroblasts from idiopathic pulmonary fibrosis (IPF) or control patients were seeded onto decelluarized lung tissue from IPF or control patients allowing for determination of gene expression differences that were driven by IPF ECM and which differences were driven by the IPF fibroblast.
GSE45734 ImmunoHuman 2015Q2 55 10 Daily sampling of peripheral blood from human subjects vaccinated for influenza was done immediately before vaccination and for 10 days after vaccination. In B cells, 90% of transcriptomic variation in subjects who received influenza vaccine within the previous three years was explained by a single temporal pattern unique to the individual. A common set of 742 genes was strongly correlated with the migration of differentiating plasma cell subtypes.
GSE45735 ImmunoHuman 2015Q2 55 10 Daily sampling of peripheral blood from human subjects vaccinated for influenza was done immediately before vaccination and for 10 days after vaccination. Temporal patterns of gene expression, determined by RNA-seq, in unfractionated PBMC suggested migration of myeloid/dendritic cell lineage cells one day after vaccination.
GSE45867 ImmunoHuman Arthritis 40 0 Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disease that is characterized by the presence of inflammatory cytokines, including interleukin-6 (IL-6). Here, we investigated the global molecular effects of Tocilizumab, an approved humanized anti-IL6 Receptor antibody, versus Methotrexate therapy, in synovial biopsy samples collected prospectively in early RA before and 12 weeks after administration of the drug. The results were compared with our previous data, generated in prospective cohorts of Adalimumab- and Rituximab-treated (Methotrexate- and anti-TNF-resistant, respectively) RA patients.\r\nWe found that Tocilizumab induces a significant down-regulation of genes included in specific pathways: cytokines & chemokines (e.g. IL-6, IL-7, IL-22, CCL8, CCL11, CCL13, CCL19, CCL20), and T cell activation. By contrast, Tocilizumab induces a significant up-regulation of genes associated with healing processes. These effects are significantly more pronounced as compared to Methotrexate, Rituximab, or Adalimumab therapies. By opposition to the effects of Adalimumab, Tocilizumab therapy does not induce a decreased expression of genes involved in cell proliferation.
GSE4588 ImmunoHuman SLE 49 4 Objective: Gene expression studies performed on PBMC from systemic lupus erythematosus (SLE) patients provided strong evidence of a type I interferon signature, underscoring the potential role of these cytokines in the physiopathology of SLE. In this work, we performed microarray analyses of differential gene expression using purified CD4 T and B cells sorted from SLE PBMC. In order to discriminate genes specific to SLE from those induced by inflammatory responses in general, control samples were obtained not only from healthy individuals but also from rheumatoid arthritis (RA) patients.\r\nResults: A strong interferon signature was found both in the CD4 T and the B lymphocytes from SLE patients, thereby confirming the results obtained on total PBMC. Interestingly, many interferon-induced genes were also over-expressed in CD4 and B cells from RA patients. Some genes were more specifically over-expressed in SLE lymphocytes, and 3 of them, SLAMF1, BRDG1 and RASGRP1, were exclusively up-regulated in SLE B cells. SLAMF1 and BRDG1 are localized in disease-associated loci, thereby suggesting that they might play a role in the physiopathology of the disease.
GSE45923 ImmunoHuman SLE 18 2 Previous studies indicate that peroxisome proliferator-activated receptor-gamma (PPAR-g) agonists suppress autoimmune responses and renal inflammation in murine lupus. However, the mechanisms implicated in this process remain unclear. We tested the effect of the PPAR-g agonist pioglitazone in human lupus and control PBMCs with regards to gene regulation and various functional assays.\r\nWe used microarrays to analyze the effect of Pioglitazone on peripheral blood cells (PBMCs) from healthy and lupus patients.
GSE46159 ImmunoHuman Asthma 8 4 Segmental allergen challenge increases the percentage of eosinophils in bronchoalveolar lavage (BAL) cells. Mepolizumab, an anti-IL-5 therapeutic antibody, decreases the number of eosinophils in bronchoalveolar lavages (BAL).\r\nThe use of both procedures allows to define genes that are either expressed by eosinophils or dependent on eosinophil presence in the airways.
GSE46171 ImmunoHuman Asthma 91 6 Acute respiratory illness (ARI) is the leading cause of asthma exacerbations yet the mechanisms underlying this association remain unclear. To address the deficiencies in our understanding of the molecular mechanisms driving ARI-induced asthma exacerbations, we undertook a transcriptional profiling study of the nasal mucosa over the course of ARI amongst individuals with a history of asthma, allergic rhinitis and no underlying respiratory disease. We found that ARI is characterized by dynamic, time-specific transcriptional profiles whose magnitudes of expression are influenced by underlying respiratory disease and the mucosal repair signature evoked during ARI. Most strikingly, we report that asthmatics that experience ARI-induced exacerbations are characterized by a reduced but prolonged inflammatory immune response, inadequate activation of mucosal repair and the expression of a newly described exacerbation-specific signature. Findings from our study represent a significant contribution towards clarifying the complex molecular interactions which typify ARI-induced asthma exacerbations.
GSE46280 ImmunoHuman 2015Q2 24 6 The purpose of this study was to investigate the expression dynamics of mRNAs and microRNAs in response to subcutaneous IFN-beta-1b treatment (Betaferon, 250 µg every other day) in patients with clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS) or relapsing-remitting type of the disease (RRMS).\r\nBy using Affymetrix microarrays, we obtained gene expression profiles of peripheral blood mononuclear cells from 6 patients within the first month of IFN-beta treatment.
GSE46451 ImmunoHuman IBD 12 4 To seek effects of inflammatory status and 5-aminosalicylic acid (5-ASA, mesalazine) exposure ex vivo on mRNA levels within rectal mucosal biopsies from patients with ulcerative colitis.
GSE46750 ImmunoHuman Arthritis 24 1 The aim of this study was to compare the gene expression pattern of synovial cells from inflammatory (I) or normal/reactive (N/R) areas of a synovial membrane harvested from the same osteoarthritis (OA) patient. This study is the first to identify different expression pattern between two areas of the synovial membrane in the same patient. These differences concern several key pathways involved in OA pathogenesis (inflammation, cartilage metabolism, Wnt signaling and angiogenesis). This analysis also provides interesting information regarding new potent intermediates as potentiel targets for the future therapeutic.
GSE46754 ImmunoHuman IBD 8 2 Our hypothesis is that in IBD patients intestinal bacteria translocation into the intra-abdominal fat depots affects adipocyte morphology and gene expression. The study aimed to study adipocyte gene expression of omental (OM) and mesenteric (MES) adipose tissue of ulcerative colitis (UC) and crohn's disease (CD).
GSE46903 ImmunoHuman superseries 384 0 Macrophage activation is associated with profound transcriptional reprogramming. Although much progress has been made in the understanding of macrophage activation, polarization and function, the transcriptional programs regulating these processes remain poorly characterized. We stimulated human macrophages with diverse activation signals, acquiring a dataset of 299 macrophage transcriptomes. Analysis of this dataset revealed a spectrum of macrophage activation states extending the current M1 versus M2-polarization model. Network analyses identified central transcriptional regulators associated with all macrophage activation complemented by regulators related to stimulus-specific programs. Applying these transcriptional programs to human alveolar macrophages from smokers and patients with chronic obstructive pulmonary disease (COPD) revealed an unexpected loss of inflammatory signatures in COPD patients. Finally, by integrating murine data from the ImmGen project we propose a refined, activation-independent core signature for human and murine macrophages. This resource serves as a framework for future research into regulation of macrophage activation in health and disease.
GSE46907 ImmunoHuman SLE 20 2 To better characterize the molecules that could potentially confer antigen presenting capacity to SLE monocytes, we assessed their gene expression profile.
GSE46911 ImmunoHuman SLE 40 10 To explore the full extent of IFN-regulated transcriptional changes, we exposed monocytes from two healthy donors to recombinant type I IFN (IFN-a2b) in vitro. RNA was extracted at different incubation times (1, 6, 24, 48 and 72 hrs) and the expression data was normalized to that of monocytes cultured with medium.
GSE46913 ImmunoHuman SLE 20 2 To directly compare the SLE monocyte transcriptional program with that of blood mDC precursors, we purified lineage HLA-DRhighCD11chigh mDCs and CD14+ monocytes from the blood of five healthy donors. Their gene expression profiles were then compared to those of blood SLE monocytes. An unsupervised clustering analysis of transcripts present in >20% of the samples classified healthy monocytes, SLE monocytes and healthy mDCs into three well defined groups. A supervised analysis was then performed to find genes: 1) differentially expressed in healthy mDCs compared to monocytes; 2) shared by healthy blood mDCs and SLE blood monocytes.
GSE46917 ImmunoHuman SLE 46 2 We screened SLE monocytes from 19 SLE patients and selected 4 that induced CD4+ T cell proliferation in vitro and 4 that did not. CFSE labeled CD4-T cells (105) were incubated with SLE monocytes (2 x 104). Cells were harvested at 6 hours for RNA extraction.
GSE46920 ImmunoHuman SLE 12 2 Monocytes from 3 healthy donors were cultured for 6 hours in the presence of 20% serum from three newly diagnosed, untreated SLE patients. Microarray analysis was then performed upon normalizing the gene expression levels of samples incubated with SLE sera to those incubated with autologous serum.
GSE46921 ImmunoHuman SLE 4 0 To explore the full extent of IFN-regulated transcriptional changes, we exposed monocytes from two healthy donors to recombinant type I IFN (IFN-a2b) in vitro. RNA was extracted at 6 hrs and the expression data was normalized to that of monocytes cultured with medium.
GSE470 ImmunoHuman Asthma 12 1 The exacerbation of disease in asthmatics has been linked to both exposure to environmental agents as well as to the presence of virus in airways, particularly rhinovirus. The hypothesis tested in these experiments is that differences in gene expression profiles in epithelial cells derived from asthmatic and normal airways can be linked to enhanced responsiveness of the epithelium in its pro-inflammatory, immulogic or other activities that may lead to the exacerbation of disease.
GSE47162 ImmunoHuman SystemicSclerosis 59 1 We identified eighty two skin transcripts significantly correlated with the severity of interstitial lung disease (ILD) in systemic sclerosis.\r\nThese genes separated patients with more sever ILD in unsupervised hierarchical clustering. Pathway analysis revealed pathways involved in extravasation and adhesion of inflammatory cells to endothelium.
GSE473 ImmunoHuman Asthma 175 4 This project is based on the hygiene hypothesis that exposure to TB provides a protective mechanism against asthma through specific cytokines and the balance of Th1, Th2 cells. Additionally, expression changes are examined in patients with and without atopy in combination with asthma and PPD status. Expression levels were evaluated in CD4+ cells isolated from peripheral blood of 30 patients. Each patient was evaluated on the entire U133 Affymetrix GeneChip set.\r\nHypothesis: That CD4+ cells have specific diagnostic profiles based upon atopy and asthma state. Further information at http://www.hopkins-genomics.org/asthma/asthma001/index.html\r\nSpecific Aim: To define diagnostic genes from purified CD4+ blood cells have specific diagnostic profiles based upon atopy and asthma state. Further information at http://www.hopkins-genomics.org/asthma/asthma001/index.html
GSE47353 ImmunoHuman 2015Q2 292 4 A major goal of systems biology is the development of models that accurately predict responses to perturbation. Constructing such models requires the collection of dense measurements of system states, yet transformation of data into predictive constructs remains a challenge. To begin to model human immunity, we analyzed immune parameters in depth both at baseline and in response to influenza vaccination.\r\nPeripheral blood mononuclear cell transcriptomes, serum titers, cell subpopulation frequencies, and B cell responses were assessed in 63 individuals before and after vaccination and were used to develop a systematic framework to dissect inter- and intra-individual variation and build predictive models of postvaccination antibody responses.\r\nStrikingly, independent of age and pre-existing antibody titers, accurate models could be constructed using pre-perturbation cell populations alone, which were validated using independent baseline time points. Most of the parameters contributing to prediction delineated temporally stable baseline differences across individuals, raising the prospect of immune monitoring before intervention.
GSE47460 ImmunoHuman COPD 582 4 Microarray data from total RNA extracted from whole lung homogenate from subjects undergoing thoracic surgery. These subjects were diagnosed as being controls or having interstitial lung disease or COPD as determined by clinical history, CT scan, and surgical pathology. There was no intervention, these are cross-sectional data. All samples are from the Lung Tissue Research Consorium (LTRC and are indexed by their LTRC tissue label).
GSE475 ImmunoHuman COPD 7 1 Diaphragm muscles in Chronic Obstructive Pulmonary Disease (COPD) patients undergo an adaptive fast to slow transformation that includes cellular adaptations. This project studies the signaling mechanisms responsible for this transformation.
GSE4757 ImmunoHuman AD 20 1 Alzheimer's Disease (AD) is a devastating neurodegenerative disorder affecting approximately 4 million people in the U.S. alone. AD is characterized by the presence of senile plaques and neurofibrillary tangles in cortical regions of the brain. These pathological markers are thought to be responsible for the massive cortical neurodegeneration and concomitant loss of memory, reasoning, and often aberrant behaviors that are seen in patients with AD. Understanding the molecular mechanisms whereby these histopathological markers develop will greatly enhance our understanding of AD development and progression. A clearer understanding of the mechanisms underlying neurofibrillary tangle formation specifically may help to clarify the basis for dementia of AD as well as the dementias associated with other diseases that are collectively referred to as "tauopathies."\r\nTo expression profile both neurons containing neurofibrillary tangles and normal neurons from the entorhinal cortex of 10 mid-stage AD cases.\r\nThe gene expression profile of neurons that contain neurofibrillary tangles will differ from the expression profile of histopathologically normal neurons from the same patient and from the same brain region. Some of these differences will be informative as to the mechanisms of tangle formation.
GSE47598 ImmunoHuman Psoriasis 24 1 Psoriasis is a Tcell-mediated disease characterized by the chronic inflammation of skin. Gene expression analyses on skin biopsies and freshly isolated PBMCs have provided important insights into Psoriasis pathophysiology.\r\nIn the present study we analyze, for the first time, the gene expression profile of in vitro activated T cells in Psoriasis compared to normal heatlhy controls.
GSE47616 ImmunoHuman SystemicSclerosis 22 7 Progressive fibrosis of the skin and internal organs accounts for the intractable nature and the high mortality of scleroderma. As the principal effector cells responsible for fibrosis, stromal fibroblasts and myofibroblasts contribute to excessive deposition of collagens and other extracellular matrix proteins. Transforming growth factor ß (TGF-ß), which stimulates collagen synthesis, myofibroblast differentiation and epithelial-mesenchymal transition (EMT), is implicated as a key initiating factor in both physiological and pathological tissue remodeling. However, the mechanism responsible for the persistence of the fibrotic process associated with pathological repair remains poorly understood. In this study, we analyzed the gene expression in dermal fibroblasts using different treatments (Poly I:C, IFN-beta, Egr-3 overexpression and other conditions).
GSE47718 ImmunoHuman COPD 17 1 Rationale: Genome-wide association studies (GWAS) and candidate gene studies have identified a number of loci linked to susceptibility of chronic obstructive pulmonary disease (COPD), a smoking-related disorder that originates in the airway epithelium.\r\nObjectives: Since airway basal cell (BC) stem/progenitor cells exhibit the earliest abnormalities associated with smoking (hyperplasia, squamous metaplasia), we hypothesized that smoker BC have a dysregulated transcriptome linked, in part, to known GWAS/candidate gene loci.\r\nMethods: Massive parallel RNA sequencing was used to compare the transcriptome of BC purified from the airway epithelium of healthy nonsmokers (n=10) and smokers (n=7). The chromosomal location of the differentially expressed genes was compared to loci identified by GWAS and candidate gene studies to confer risk for COPD.\r\nMeasurements and Main Results: Smoker BC have 676 known genes differentially expressed compared to nonsmoker BC, dominated by smoking up-regulation. Strikingly, 166 (25%) of these genes are located on chromosome 19, with 13 localized to 19q13.2 (p<10-4 compared to chance), including TGFB1, LTBP4, EGLN2 and NFKBIB, genes associated with risk for COPD.\r\nConclusions: These observations provide the first direct link of known genetic risks for smoking-related lung disease with the specific population of lung cells that undergoes the earliest changes associated with smoking.
GSE47726 ImmunoHuman 2015Q2 11 1 Synovial biopsies of Rheumatoid Arthritis patients with active disease were obtained prior to anti-TNF therapy. Clinical response to anti-TNF treatment was measured 20 weeks later using the EULAR response criteria.\r\nGene expression profiles of patients responding to anti-TNF therapy were compared to non-responders and several genes were found to be differentially expressed between both groups of Rheumatoid Arthritis patients.
GSE47751 ImmunoHuman 2015Q2 34 5 Anti-TNF-alpha therapy has made a significant impact on the treatment of psoriasis. Despite being designed to neutralize TNF-alpha activity, the mechanism of action of these agents in the resolution of psoriasis remains unclear. The aim of this study was to better understand the mechanism of action of etanercept by examining very early changes in the lesional skin of psoriasis patients. 20 chronic plaque psoriasis patients were enrolled and received 50mg etanercept twice weekly. Skin biopsies were obtained before treatment and on days 1, 3, 7 and 14 post-treatment. Skin mRNA expression was analysed by microarray.
GSE47855 ImmunoHuman nomodel 30 0 A small subset of T cells also expresses kiler-cell immunoglobulin-like receptors (KIRs). We find that KIR+ T cells primarily reside in the CD56+ T population. However, little is known on how these cells are different from the conventional CD56- T, NK, and iNKT cells.\r\nWe used microarray profiling to compare and determine the distinctive differences of CD56+ T cell and its KIR subsets when compared to the conventional CD56- T, NK and iNKT cells.
GSE47944 ImmunoHuman 2015Q2 84 17 Environmental stimuli are known to contribute to psoriasis pathogenesis and that of other autoimmune diseases, but the mechanism is unknown. Here we show that the aryl hydrocarbon receptor (AhR), a transcription factor that senses environmental stimuli, modulates pathology in psoriasis. AhR-activating ligands reduced inflammation in the lesional skin of psoriasis patients, whereas AhR antagonists upregulated inflammation. Similarly, AhR signaling via the endogenous FICZ ligand reduced the inflammatory response in the imiquimod-induced model of psoriasis and AhR deficient mice exhibited a substantial exacerbation of the disease, compared to AhR sufficient controls. Non-haematopoietic cells, in particular keratinocytes, were responsible for this hyper-inflammatory response, which involved increased reactivity to IL-1beta and upregulation of AP-1 family members of transcription factors. Thus, our data suggest a critical role for AhR in the regulation of inflammatory responses and open the possibility for novel therapeutic strategies in chronic inflammatory disorders.
GSE48006 ImmunoHuman Arthritis 18 2 The transition of the endothelium to a pro-inflammatory state is key to progression of chronic inflammatory diseases including rheumatoid arthritis, chronic bowel disease and atherosclerosis. In atherosclerosis it is hypothesized that low density lipoproteins (LDL) that become trapped in the intima of the blood vessels are oxidized to minimally modified LDL (mmLDL) and that these serve as an important contributing factors to endothelial dysfunction. Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine (OX-PAPC), a model of the active phospholipid components of mmLDL affects the expression of hundreds of genes involved in inflammatory and other biological processes in human aortic endothelial cells (HAECs). We hypothesized that microRNAs (miRNAs) partially regulate this response. Using next generation sequencing, we identified miR-21-3p and miR-27a-5p to be induced 4-fold and 3-fold, respectively in response to OX-PAPC treatment compared to control treatment in HAECs. To identify the targets, we performed whole genome transcript profiling following transient over-expression of these two miRNAs followed by. In total, 1254 genes were down-regulated with 925 of them overlapping between the two miRNAs. Functional enrichment analysis using Gene Ontology predicted that the two miRNAs were involved in the regulation of NF-?B signaling. We characterized the Toll/interleukin-1 receptor (TIR) domain-containing adaptor protein TICAM2 as a direct target of miR-21-3p and miR-27a-5p. Furthermore, we showed that over-expression of miR-21-3p and miR-27a-5p lead to decreased p65 translocation to the nucleus and decreased the expression of known NF-?B downstream target genes confirming both miRNAs’ role in negatively regulating NF-?B signaling in endothelial cells.
GSE48018 ImmunoHuman 2015Q2 431 3 The purpose of the study was to assess the patterns of global gene expression in peripheral blood cells before and at three time points after the administration of a trivalent influenza vaccine in human male subjects, and to relate these to the antibody response to the vaccine. The antibody titer data for these subjects is provided as a supplemental file.
GSE48023 ImmunoHuman 2015Q2 417 3 The purpose of the study was to assess the patterns of global gene expression in peripheral blood cells before and at three time points after the administration of a trivalent influenza vaccine in human female subjects, and to relate these to the antibody response to the vaccine
GSE48149 ImmunoHuman SystemicSclerosis 53 4 Objective: Pulmonary complications in systemic sclerosis (SSc), including pulmonary fibrosis (PF) and pulmonary arterial hypertension (PAH), are the leading cause of mortality. We compared the molecular fingerprint of SSc lung tissues and matching primary lung fibroblasts to those of normal donors, and patients with idiopathic pulmonary fibrosis (IPF) and idiopathic pulmonary arterial hypertension (IPAH). Methods: Lung tissues were obtained from 33 patients with SSc who underwent lung transplantation. Tissues and cells from a subgroup of SSc patients with predominantly PF or PAH were compared to those from normal donors, patients with IPF, or IPAH. Microarray data was analyzed using Efficiency Analysis for determination of optimal data processing methods. Real time PCR and immunohistochemistry were used to confirm differential levels of mRNA and protein, respectively. Results: We identified a consensus of 242 and 335 genes that were differentially expressed in lungs and primary fibroblasts, respectively. Enriched function groups in SSc-PF and IPF lungs included fibrosis, insulin-like growth factor signaling and caveolin-mediated endocytosis. Functional groups shared by SSc-PAH and IPAH lungs included antigen presentation, chemokine activity, and IL-17 signaling. Conclusion: Using microarray analysis on carefully phenotyped SSc and comparator lung tissues, we demonstrated distinct molecular profiles in tissues and fibroblasts of patients with SSc-associated lung disease compared to idiopathic forms of lung disease. Unique molecular signatures were generated that are disease- (SSc) and phenotype- (PF vs PAH) specific. These signatures provide new insights into pathogenesis and potential therapeutic targets for SSc lung disease.
GSE48200 ImmunoHuman Influenza 18 5 Gene transcription effects of mutations in the infuenza virus A/Hong Kong/1/1968(H3N2) nonstructural 1 NS1 gene in infected human A549 (lung epithilium) cells\r\nInfluenza A/Hong Kong/156/1997(H5N1) virus NS1 gene mutations F103L and M106I both increase IFN antagonism, virulence and cytoplasmic localization but differ in binding to RIG-I and CPSF30 (manuscript submitted to Virology Journal). Human cells were infected with influenza viruses mutants with specific gain of function mutations in the NS1 gene in order to assess the affects of each mutation on host gene expression. Human (A549) and mouse (M1) cells were infected at a multiplicity of infection of 2 (infectious viruses/cell) and incubated for 8 hr before collection of total RNA and microarray anlaysis using the Affymetrix platforms. Samples were compared in triplicate to mock PBS infected (uninfected) cells to detecte dysregulated genes for A/HK/1/1968(H3N2) wt, and the following NS1 gene mutants: F103L, M106I, M106V, and F103L + M106I.\r\nBackground: The genetic basis for avian to mammalian host switching in influenza A virus is largely unknown. The human A/HK/156/1997(H5N1) virus that transmitted from poultry possesses NS1 gene mutations F103L + M106I that are virulence determinants in the mouse model of pneumonia; however their individual roles have not been determined. The emergent A/Shanghai/1/2013(H7N9)-like viruses also possess these mutations which may contribute to their virulence and ability to switch species.\r\nMethods: NS1 mutant viruses were constructed by reverse genetics and site directed mutagenesis on human and mouse-adapted backbones. Mouse infections assessed virulence, virus yield, tissue infection, and IFN induction. NS1 protein proprieties were assessed for subcellular distribution, IFN antagonism (mouse and human), CPSF30 and RIG-I domain binding, effect on host gene transcription (microarray); and the natural prevalence of 103L and 106I mutants was assessed.\r\nResults: Each of the F103L and M106I mutations contributes additively to virulence to reduce the lethal dose by >800 and >3,200 fold respectively by mediating alveolar tissue infection with >100 fold increased infectious yields. The 106I NS1 mutant lost CPSF binding but the 103L mutant maintained binding that correlated with an increased general decrease in host gene expression in human but not mouse cells. Each mutation positively modulated the inhibition of IFN induction in mouse cells and activation of the IFN-ß promoter in human cells but not in combination in human cells indicating negative epistasis. Each of the F103L and M106I mutations restored a defect in cytoplasmic localization of H5N1 NS1 in mouse cells. Human H1N1 and H3N2 NS1 proteins bound to the CARD, helicase and RD RIG-I domains, whereas the H5N1 NS1 with the same consensus 103F and 106M mutations did not bind these domains, which was partially or totally restored by the F103L or M106I mutations respectively.\r\nConclusions: The F103L and M106I mutations in the H5N1 NS1 protein each increased IFN antagonism and mediated interstitial pneumonia in mice that was associated with increased cytoplasmic localization and altered host factor binding. These mutations may contribute to the ability of previous HPAI H5N1 and recent LPAI H7N9 viruses to switch hosts and cause severe disease in mammals.
GSE4828 ImmunoHuman 2015Q2 8 1 In inflamed tissue, normal signal transduction pathways are altered by extracellular signals. For example, the JNK pathway is activated in psoriatic skin, which makes it an attractive target for treatment. To define comprehensively the JNK-regulated genes in human epidermal keratinocytes, we compared the transcriptional profiles of control and JNK inhibitor-treated keratinocytes, using DNA microarrays. We identified the differentially expressed genes 1, 4, 24 and 48 hrs after the treatment with SP600125. Surprisingly, the inhibition of JNK in keratinocyte cultures in vitro induces virtually all aspects of epidermal differentiation in vivo: transcription of cornification markers, inhibition of motility, withdrawal from the cell cycle, stratification and even production of cornified envelopes. The inhibition of JNK also induces the production of enzymes of lipid and steroid metabolism, proteins of the diacylglycerol and inositol-phosphate pathways, mitochondrial proteins, histones and DNA repair enzymes, which have not been associated with differentiation previously. Simultaneously, basal cell markers, including integrins, hemidesmosome and ECM components, are suppressed. Promoter analysis of regulated genes finds that the binding sites for the forkhead family of transcription factors are over-represented in the SP600125-induced genes, and c-Fos sites in the suppressed genes. The JNK-induced proliferation appears to be secondary to inhibition of differentiation. The results indicate that the inhibition of JNK in epidermal keratinocytes is sufficient to initiate their differentiation program, and suggest that augmenting JNK activity could be used to delay cornification and enhance wound healing, while attenuating it could be a differentiation therapy-based approach for treating psoriasis.
GSE48350 ImmunoHuman AD 253 4 This dataset contains microarray data from normal controls (aged 20-99 yrs) and Alzheimer's disease cases, from 4 brain regions: hippocampus, entorhinal cortex, superior frontal cortex, post-central gyrus. Changes in expression of synaptic and immune related genes were analyzed, investigating age-related changes and AD-related changes, and region-specific patterns of change.\r\nThese AD cases were processed simultaneously with the control cases (young and aged) included in GSE11882 (GSE11882 dataset contains data exclusively from normal control brains).
GSE48466 ImmunoHuman Influenza 12 3 We used microarrays to compare the gene expression profiles of different H1N1 isolates (seasonal and pandemic) in lung epithelial cells in vitro.
GSE48556 ImmunoHuman Arthritis 139 1 By performing a comprehensive exploration of peripheral blood by microarray analysis from a subset of the Genetics osteoarthritis and Progression (GARP) study in comparison with sex and age-matched healthy controls we have identified disease specific gene expression networks. Our data hint at the relevance of apoptosis as an etiological factor in osteoarthritis onset, thereby qualifying expression profiling of blood as a useful tool to understand the underlying molecular mechanisms of osteoarthritis.
GSE48586 ImmunoHuman Psoriasis 12 3 We show that exposure of artificial human skin tissue to intense, picosecond-duration THz pulses affects expression levels of numerous genes associated with non-melanoma skin cancers, psoriasis and atopic dermatitis. Genes affected by intense THz pulses include nearly half of the epidermal differentiation complex (EDC) members. EDC genes, which are mapped to the chromosomal human region 1q21, encode for proteins that partake in epidermal differentiation and are often overexpressed in conditions such as psoriasis and skin cancer. In nearly all the genes differentially expressed by exposure to intense THz pulses, the induced changes in transcription levels are opposite to disease-related changes.
GSE48757 ImmunoHuman ChronicInflammation 6 1 Human skin-derived precursor cells (hSKP) are a stem cell population that represents key candidates for cell based-therapy. Inflammation, however, is often present in situations where cellular replacement therapy is required. These inflammatory conditions, and more specifically the presence of the cytokine interferon (IFN)-?, might result in an increase of MHC class II antigens in hSKP-derived grafts and facilitate their rejection.\r\nWe used microarray analyses to confirm the activated status of the pro-inflammatory condition, induced by exposure to a cocktail of pro-inflammatory cytokines (IL-1ß, IFN-?, TNFa and IFN-a). Consequently, we investigated the modulation by inflammation of canonical pathways related to immunology in hSKP.
GSE48762 ImmunoHuman 2015Q2 621 41 The objective of this study is to: 1) Characterize the immune responsiveness to administration of non-live vaccines in three cohorts of healthy adult subjects through the analysis of blood leukocytes transcriptional profiles. 2) Validate whole blood transcriptional profiles generated from standard 3mL blood draws versus 200uL blood draws obtained by finger stick. 3) Discover potential biomarkers for immune-responsiveness to non-live vaccines.
GSE48780 ImmunoHuman Arthritis 83 0 Rheumatoid arthritis (RA) is a complex and clinically heterogeneous autoimmune disease.\r\nMicroarray analysis of 83 synovial samples provides insight into the expression-level differences between patients at the site of disease activity.
GSE48958 ImmunoHuman IBD 21 2 In this study, we investigated if miRNA expression in UC mucosa is altered and correlated our findings with mucosal mRNA expression. Integration of mRNA and miRNA expression profiling may allow the identification of functional links between dysregulated miRNAs and their predicted target mRNA.
GSE48978 ImmunoHuman NormalControl 12 5 Samples in this study probe the gene expression kinetics in human CCR6+ Th17 memory T cells activated under Th17 condition. Human CCR6+ Th17 memory T cells were purified from PBMC and gene expression was studied over a time course of 3 days after activation under Th17 condition. RNA from these samples was also profiled using RNA-Seq to compare different transcriptome profiling technologies.
GSE49036 ImmunoHuman PD 28 3 Subjects with incidental Lewy body disease (iLBD) may represent the premotor stage of Parkinson’s disease (PD). To identify molecular mechanisms underlying neuronal dysfunction and alpha--synuclein pathology in the premotor phase of PD, we investigated the transcriptome of post-mortem substantia nigra (SN) of iLBD, PD donors and age-matched controls with Braak alpha--synuclein stage ranging from 0-6. In Braak alpha--synuclein stages 1 and 2, we observed deregulation of pathways linked to axonal degeneration, unfolded protein response (UPR), immune response and endocytosis, including axonal guidance signaling, protein kinase A signaling, mTOR signaling, EIF2 signaling and clathrin-mediated endocytosis. In Braak stages 3 and 4, we observed a deregulation in pathways involved in protein translation and cell survival, including mTOR and EIF2 signaling. In Braak stages 5 and 6, we observed deregulation of pathways such as dopaminergic signaling, axonal guidance signaling and thrombin signaling. Throughout the progression of PD pathology, we observed a deregulation of mTOR, EIF2 and regulation of eIF4 and p70S6K signaling in the SN. This implicates that molecular mechanisms related to UPR, axonal dysfunction, endocytosis and immune response are an early event in PD pathology, and may hold the key to altering the disease progression in PD.
GSE49072 ImmunoHuman PulmonaryFibrosis 84 3 Gene expression profiles for patients affected with Sporadic and Familial Pulmonary Fibrosis.
GSE49454 ImmunoHuman SLE 177 1 Gene expression profiling (compared to healthy controls) to identify patients with active SLE disease and patients with quiescent disease
GSE49604 ImmunoHuman Arthritis 12 4 Rheumatoid synoviocytes, which consist of fibroblast-like synoviocytes (FLS) and synovial macrophages (SM), are crucial for the progression of rheumatoid arthritis (RA). Particularly, FLS of RA patients (RA-FLS) exhibit invasive characteristics reminiscent of cancer cells, destroying cartilage and bone, although it remains unresolved how RA-FLS exhibit invasive phenotype. RA-FLS and SM originate differently from mesenchymal and myeloid cells, respectively, but share many pathologic functions. However, the molecular signatures and biological networks representing the distinct and shared features of the two cell types are unknown. Presently, we performed global transcriptome profiling of FLS and SM obtained from RA and osteoarthritis patients. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining invasiveness of RA-FLS and pro-inflammatory properties of RA synovial macrophages (RA-SM), respectively. Interestingly, under interleukin1β-stimulated condition, RA-FLS newly acquired pro-inflammatory signature mimicking RA-SM without losing invasive properties. We next reconstructed a network model that delineates the shared, RA-FLS-dominant (invasive), and RA-SM-dominant (inflammatory) processes. From the network model, we selected 13 genes, including POSTN and TWIST1, as novel regulator candidates responsible for FLS invasiveness. Of note, POSTN and TWIST1 expressions were elevated in independent RA-FLS and were further instigated by interleukin1β. In vitro functional assays demonstrated the requirement of POSTN and TWIST1 for migration and invasion of RA-FLS stimulated with interleukin1β. Taken together, our systems approach to rheumatoid synovitis provides a basis for identifying novel regulators responsible for pathological features of RA-FLS and RA-SM, demonstrating how a certain type of cells acquires functional redundancy under chronic inflammatory conditions.
GSE49706 ImmunoHuman Inflammation 12 5 Here we investigate how glucocorticoids affect the response to Interferon gamma in human macrophages.
GSE49709 ImmunoHuman Inflammation 12 2 Here we investigate how glucocorticoids affect the response to LPS in human macrophages.
GSE49840 ImmunoHuman Influenza 78 16 A novel avian-origin H7N9 influenza A virus (IAV) emerged in China in early 2013 causing mild to lethal human respiratory infections. H7N9 originated from multiple reassortment events between avian viruses and carries genetic markers of human adaptation. Determining whether H7N9 induces a host-response closer to human or avian IAV is important to better characterize this emerging virus. Here we compared the human lung epithelial cell response to infection with A/Anhui/01/13 (H7N9) or highly pathogenic avian-origin H5N1, H7N7, or human seasonal H3N2 IAV.
GSE49853 ImmunoHuman BasicScience 4 1 To determine characterize human B cells that express IL-10 on a molecular level, we compared the global gene expression of primary CD19pos B cells secreting IL-10 or not, upon activation with anti-CD40, IL-4 and CpG for 2 days.
GSE49877 ImmunoHuman IBD 36 3 The intestinal mucosa harbors the largest accumulation of T lymphocytes in the body. While these T cells play an important role in immune homeostasis, they are also implicated in triggering and maintaining pathological intestinal inflammation. In humans they are poorly characterised, and even mouse transcriptomes have been reported for only a few individual cell types, many of which lack direct human equivalents. Using expression microarrays on T cells isolated from ileal biopsies and in silico analysis, we present here an unbiased, transcriptome-wide view of function in T cell subpopulations of the healthy human intestine and delineate signalling pathways that are distinct from those seen in peripheral blood T cells.
GSE50175 ImmunoHuman NormalControl 8 1 We previously demonstrated that Th1Th17 cells are highly permissive to HIV-1, whereas Th1 cells are relatively resistant. Here, we investigated molecular mechanisms underlying these differences. Superior HIV replication in Th1Th17 vs. Th1 cells was regulated by entry and post-entry mechanisms.\r\nWe used microarrays to detail the gene expression signatures caracterizing Th1 cells from Th1Th17.
GSE50380 ImmunoHuman IBD 11 2 This file contains gene microarray data from subsets of human intestinal dendritic cells, as defined by their expression of CD103 and Sirpa. This will allow for better understanding of human intestinal DC subsets in general and will facilitate translation from findings in the mouse.
GSE50395 ImmunoHuman SLE 12 3 The present gene expression array study of comparative gene profile in monocytes from patients with primary Antiphospholipid Syndrome, Systemic Lupus Erythematosus and Lupus with Antiphospholipid Syndrome demonstrates that the gene expression profiling allows the segregation of these highly related autoimmune diseases, with specific signatures explaining the pro-atherosclerotic, pro-thrombotic and inflammatory changes.
GSE5056 ImmunoHuman COPD 44 1 Upregulation of Expression of the Ubiquitin Carboxyl Terminal Hydrolase L1 Gene in Human Airway Epithelium of Cigarette Smokers\r\nThe microarray data deposited here is from 44 HuGeneFL GeneChips, from 9 normal non-smokers and 13 phenotypic normal smokers, large airways, 2 samples per individual, one from the right lung and one from the left lung. These samples were previously described in Hackett NR, Heguy A, Harvey BG, O'Connor TP, Luettich K, Flieder DB, Kaplan R, Crystal RG. Variability of antioxidant-related gene expression in the airway epithelium of cigarette smokers. Am J Respir Cell Mol Biol. 2003 29:331-43 and in Heguy A, Harvey BG, O'Connor TP, Hackett NR, Crystal RG. Sampling-dependent up-regulation of gene expression in sequential samples of human airway epithelial cells. Mol Med. 2003 9:200-8. These data are part of a study aimed at understanding how cigarette smoking modifies neuroendocrine cells, in which microarray analysis with TaqMan confirmation was used to assess airway epithelial samples obtained by fiberoptic bronchoscopy from 81 individuals (normal nonsmokers, normal smokers, smokers with early COPD and smokers with established COPD). Of 11 genes considered to be neuroendocrine cell-specific, only ubiquitin C-terminal hydrolase L1(UCHL1), a member of the ubiquitin proteasome pathway, was consistently upregulated in smokers compared to nonsmokers. Up-regulation of UCHL1 at the protein level was observed with immunohistochemistry of bronchial biopsies of smokers compared to nonsmokers. Interestingly, however, while UCHL1 expression was present only in neuroendocrine cells of the airway epithelium in nonsmokers, UCHL1 expression was also expressed in ciliated epithelial cells in smokers, an intriguing observation in light of recent observations that ciliated cells can are capable of transdifferentiating to other airway epithelium. In the context that UCHL1 is involved in the degradation of unwanted, misfolded or damaged proteins within the cell and is overexpressed in >50% of lung cancers, its overexpression in chronic smokers may represent an early event in the complex transformation from normal epithelium to overt malignancy.
GSE5057 ImmunoHuman COPD 11 1 Upregulation of Expression of the Ubiquitin Carboxyl Terminal Hydrolase L1 Gene in Human Airway Epithelium of Cigarette Smokers\rThe microarray data deposited here is from 11 HG-U133A GeneChips, from 5 normal non-smokers and 6 phenotypic normal smokers, large airways. Samples from the small airways of these individuals have been obtained and analyzed using the HG-U133A GeneChip; the small airway samples are in GEO Accession Number GSE 3320, and the data analysis is described in Harvey, B-G; Heguy, A.; Leopold, P.L.; Carolan, B.; Ferris, B. and Crystal R.G. Modification of Gene Expression of the Small Airway Epithelium in Response to Cigarette Smoking. J. Mol. Med (in press). These data are part of a study aimed at understanding how cigarette smoking modifies neuroendocrine cells, in which microarray analysis with TaqMan confirmation was used to assess airway epithelial samples obtained by fiberoptic bronchoscopy from 81 individuals (normal nonsmokers, normal smokers, smokers with early COPD and smokers with established COPD). Of 11 genes considered to be neuroendocrine cell-specific, only ubiquitin C-terminal hydrolase L1(UCHL1), a member of the ubiquitin proteasome pathway, was consistently upregulated in smokers compared to nonsmokers. Up-regulation of UCHL1 at the protein level was observed with immunohistochemistry of bronchial biopsies of smokers compared to nonsmokers. Interestingly, however, while UCHL1 expression was present only in neuroendocrine cells of the airway epithelium in nonsmokers, UCHL1 expression was also expressed in ciliated epithelial cells in smokers, an intriguing observation in light of recent observations that ciliated cells can are capable of transdifferentiating to other airway epithelium. In the context that UCHL1 is involved in the degradation of unwanted, misfolded or damaged proteins within the cell and is overexpressed in >50% of lung cancers, its overexpression in chronic smokers may represent an early event in the complex transformation from normal epithelium to overt malignancy.
GSE5058 ImmunoHuman COPD 38 2 Upregulation of Expression of the Ubiquitin Carboxyl Terminal Hydrolase L1 Gene in Human Airway Epithelium of Cigarette Smokers\r\nThe microarray data deposited here is from 39 HG-U133 Plus 2.0 GeneChips, from 12 normal non-smokers, 12 phenotypic normal smokers, 9 Early COPD and 6 COPD individuals, all small airways, all small airway. A subset of these samples have been already submitted under GEO Accession Number GSE 4498. These are: 12 non-smokers samples (GSM101095-GSM101106) and 10 smoker samples (GSM101107-GSM101116). These 22 samples that are also in GSE4498 were described in Harvey, B-G; Heguy, A.; Leopold, P.L.; Carolan, B.; Ferris, B. and Crystal R.G. Modification of Gene Expression of the Small Airway Epithelium in Response to Cigarette Smoking. J. Mol. Med (in press). These data are part of a study aimed at understanding how cigarette smoking modifies neuroendocrine cells, in which microarray analysis with TaqMan confirmation was used to assess airway epithelial samples obtained by fiberoptic bronchoscopy from 81 individuals (normal nonsmokers, normal smokers, smokers with early COPD and smokers with established COPD). Of 11 genes considered to be neuroendocrine cell-specific, only ubiquitin C-terminal hydrolase L1(UCHL1), a member of the ubiquitin proteasome pathway, was consistently upregulated in smokers compared to nonsmokers. Up-regulation of UCHL1 at the protein level was observed with immunohistochemistry of bronchial biopsies of smokers compared to nonsmokers. Interestingly, however, while UCHL1 expression was present only in neuroendocrine cells of the airway epithelium in nonsmokers, UCHL1 expression was also expressed in ciliated epithelial cells in smokers, an intriguing observation in light of recent observations that ciliated cells can are capable of transdifferentiating to other airway epithelium. In the context that UCHL1 is involved in the degradation of unwanted, misfolded or damaged proteins within the cell and is overexpressed in >50% of lung cancers, its overexpression in chronic smokers may represent an early event in the complex transformation from normal epithelium to overt malignancy.
GSE5059 ImmunoHuman COPD 7 1 Upregulation of Expression of the Ubiquitin Carboxyl Terminal Hydrolase L1 Gene in Human Airway Epithelium of Cigarette Smokers\r\nThe microarray data deposited here is from 9 HG-U133 Plus 2.0 GeneChips, from 4 normal non-smokers, and 5 phenotypic normal smokers, all large airways. These data are part of a study aimed at understanding how cigarette smoking modifies neuroendocrine cells, in which microarray analysis with TaqMan confirmation was used to assess airway epithelial samples obtained by fiberoptic bronchoscopy from 81 individuals (normal nonsmokers, normal smokers, smokers with early COPD and smokers with established COPD). Of 11 genes considered to be neuroendocrine cell-specific, only ubiquitin C-terminal hydrolase L1(UCHL1), a member of the ubiquitin proteasome pathway, was consistently upregulated in smokers compared to nonsmokers. Up-regulation of UCHL1 at the protein level was observed with immunohistochemistry of bronchial biopsies of smokers compared to nonsmokers. Interestingly, however, while UCHL1 expression was present only in neuroendocrine cells of the airway epithelium in nonsmokers, UCHL1 expression was also expressed in ciliated epithelial cells in smokers, an intriguing observation in light of recent observations that ciliated cells can are capable of transdifferentiating to other airway epithelium. In the context that UCHL1 is involved in the degradation of unwanted, misfolded or damaged proteins within the cell and is overexpressed in >50% of lung cancers, its overexpression in chronic smokers may represent an early event in the complex transformation from normal epithelium to overt malignancy.
GSE5060 ImmunoHuman superseries 121 0 This SuperSeries is composed of the SubSeries listed below.
GSE50614 ImmunoHuman 2015Q2 22 4 Activation of Sirtuin (silent mating type information regulation 2 homolog) 1, or SIRT1, is an unexplored therapeutic approach for treatment of inflammatory diseases. The goal of this study was to evaluate the clinical activity and tolerability of multiple doses of SRT2104, a selective activator of SIRT1, in patients with moderate to severe psoriasis after day 84 of treatment. Forty patients were randomized 4:1 to three escalating doses of SRT2104 (250, 500, 1000 mg/d SRT2104 or placebo). Across all SRT2104 groups, 34.6% of patients (9 out of 26; 90% CI 18.0%-54.2%, p<0.0001) achieved good to excellent histological improvement based on skin biopsies taken at baseline and day 84. To evaluate the changes in expression profile with treatment and to identify pathways involved in histological improvement, a subset of 22 Pre and Post treatment biopsies from 11 patients (4 Placebo, 7 Active Treatment) were hybridized to hgu133plus2 chips. Improvement in histology was associated with modulation of IL-17 and TNF-_ signaling pathways and keratinocyte differentiation target genes. Various studies suggest a crucial role of TNF_ and IL-17 in psoriasis pathogenesis and IL-17/TNF_ synergism induces a strong induction of differentially expressed genes in psoriasis, thus advocating a crucial role of IL-17/TNF_ combination in the molecular basis of disease (Chiricozzi et al., 2010). In the current study, broad scale gene expression profiling revealed that SRT2104 significantly reduced known IL-17 and TNF_ responsive genes including SERPINB4, S100A12, SERPINB3, kynu etc. even though the sample size for this analysis was small. One of the most highly modulated genes by SRT2104 included Kynu, a gene that regulates tryptophan metabolism, known to confer antibacterial effector functions (Daubener and MacKenzie, 1999). Interestingly kynu is part of the etanercept residual genomic profile that is not modulated by etanercept therapy even though clinical efficacy is achieved. Possibly, SRT2104 may be modulating the lipid barrier of the epidermis of psoriatic skin via modulation of keratinocyte diferentiation genes, which would be consistent with the observed improvement in skin histology. These results indicate a combinatorial effect of SRT2104 on TNF_, and IL-17 inflammatory signaling pathways and keratinocyte differentiation that could be a contributing factor towards improvement in clinical scores by the SIRT1 activator, SRT2104.
GSE50628 ImmunoHuman Influenza 32 4 The differences of clinical characteristics in complex seizures induced by influenza A(H1N1)pdm09 and rotavirus gastroenteritis are well known, but the pathogenic mechanisms remain unclear. We analyzed the gene expression profiles in the peripheral whole blood cells isolated from pediatric patients using an Affymetrix oligonucleotide microarray.\r\nResults provide insights into the difference of the pathogenesis in the patients with complex seizures induced by influenza A(H1N1)pdm09 and rotavirus infections.
GSE50635 ImmunoHuman SLE 49 2 Systemic lupus erythematosus (SLE) is a heterogeneous disease which leads to different levels of serum autoantibodies to RNA-binding proteins (anti-RBP) and interferon-a (IFN-a), which plays an important pathogenic role in SLE, between European-American (EA) and African-American (AA) patients. We aimed to explore how IFN-related gene expression pathways differ in patients according to their ancestry and anti-RBP profile
GSE50772 ImmunoHuman SLE 81 1 Peripheral blood mononuclear cells were collected from SLE patients in an observational study performed at the University of Michigan\r\nBlood microarray expression data were used to confirm the presence of an Interferon signature and identify additional surrogate genes
GSE50788 ImmunoHuman IBD 36 4 A total proctocolectomy with ileal pouch-anal anastomosis (IPAA) is considered the surgery of choice for definitive management of familial adenomatous polyposis (FAP) and selected patients with ulcerative colitis (UC). However, this surgical treatment often associates with a long-term complication, pouchitis, which occurs mostly in UC patients.\r\nTo better define the molecular background of pouchitis, the microarray-based survey was performed using pouch mucosal samples collected from 28 and 8 patients operated for UC and FAP, respectively. A number of 4771 genes was significantly differentiating uninflamed from inflamed mucosal samples, and their functional features were represented mostly by alerted metabolic and cell proliferation pathways. In contrast, functional analyses of aberrantly expressed probe sets between UC and FAP samples, irrespectively of mucosal inflammation status, revealed multiple pathways and terms which were linked to changes in immune response. Noteworthy, the comparison of uninflamed UC and FAP samples distinguished a set of 26 altered mRNAs including inflammation-related transcript encoding a Charcot-Leyden crystal (CLC) protein. The most discrete changes in gene expression profiles differentiating uninflamed UC and FAP mucosal samples were attributed to a Gene Ontology category innate immune response.\r\nOur study confirmed alterations of the immune responses as dominant in UC pouchitis which were earlier found in the studies using analyses of singular molecular elements. This observation may be important when managing IPAA patients.
GSE50790 ImmunoHuman Psoriasis 8 1 Psoriasis is a chronic inflammatory skin disease characterized by marked proliferation of keratinocytes leading to pronounced epidermal hyperplasia, elongation of rete ridges and hyperkeratosis. The most common form of psoriasis, chronic plaque psoriasis (Psoriasis vulgaris), involves relatively stable occurrence and progression of sharply demarcated lesions, usually on the trunk and extremities, which share a combination of trademark histological features, including tortuous and dilated dermal capillaries, loss of the epidermal granular layer, and accumulation of neutrophils beneath parakeratotic scale. In this study, whole-genome transcriptional profiling was used to characterize gene expression in 4 lesional and uninvolved skin samples obtained from patients with stable chronic plaque psoriasis.Skin mRNA expression was analysed by microarray.
GSE51392 ImmunoHuman Asthma 68 6 Rhinovirus infections are the most common cause of asthma exacerbations. The complex responses by the airway epithelium to rhinovirus can be captured by gene expression profiling. We hypothesized that the upper and lower airway epithelium exhibit differential responses to double-stranded RNA (dsRNA), and that this is modulated by the presence of asthma and allergic rhinitis.\r\nIdentification of dsRNA-induced gene expression profiles by microarray of primary nasal and bronchial epithelial cells from the same individuals and examining the impact of allergic rhinitis with and without concomitant allergic asthma on expression profiles.
GSE51404 ImmunoHuman LungDisease 53 3 Transcriptional profiling was used to characterize the immunologic networks in subjects with CVID who have inflammatory complications to identify clues as to pathogenesis and potentially better modes of treatment.
GSE51405 ImmunoHuman LungDisease 83 5 Transcriptional profiling was used to characterize the immunologic networks in subjects with CVID who have inflammatory complications to identify clues as to pathogenesis and potentially better modes of treatment.
GSE51440 ImmunoHuman Psoriasis 59 3 A gene expression profiling study was conducted in which skin biopsy samples were collected for RNA extraction and hybridization to microarrays from patients with moderate-to-severe psoriasis who participated in the phase 1, guselkumab first-in-human randomized, double-blind, placebo-controlled trial.\r\nAt week 12, significant reductions in psoriasis gene expression were observed in guselkumab-treated patients.
GSE5145 ImmunoHuman Asthma 6 1 Studied gene regulation in bronchial smooth muscle cells following vitamin D stimulation.
GSE51588 ImmunoHuman Arthritis 50 2 To date, all of the prior osteoarthritic microarray studies in human tissue have focused on the overlying articular cartilage, meniscus, or synovium but not the underlying subchondral bone. In our previous study, our group developed a methodology for high quality RNA isolation from site-matched cartilage and bone from human knee joints, which allowed us to perform candidate gene expression analysis on the subchohndral bone (published on Osteoarthritis and Cartilage on Dec/5/2012 (doi: 10.1016/j.joca.2012.11.016). To the best of our knowledge, the current study is the first to successfully perform whole-genome microarray profiling analyses of human osteoarthritic subchondral bone. We believe our comprehensive microarray results can improve the understanding of the pathogenesis of osteoarthritis and could further contribute to the development of new biomarker and therapeutic strategies in osteoarthritis.
GSE51684 ImmunoHuman ALS 24 4 Purpose: The purpose of this experiment is to identify a C9-ALS/FTD specific genomic profile in fibroblast lines that is distinct from sporadic ALS without C9orf72 expansion and non-neurologic control cells. The study will then evaluate the effect on this identified profile of ASO treatment targeting the sense strand RNA transcript of the C9orf72 gene.\r\nMethods: Expression profiling was performed on RNAs from fibroblasts of four C9orf72 patients, four control individuals and four sporadic ALS patients using Multiplex Analysis of PolyA-linked Sequences method.\r\nResults: Hierarchical clustering of expression values for all genes showed that the four C9orf72 patient lines had an expression profile distinct from control and sporadic ALS lines. Statistical comparison of expression values between the four C9orf72 lines and the four control lines revealed that 122 genes were upregulated (defined by a False Discovery Rate FDR<0.05) and 34 genes were downregulated (defined by a False Discovery Rate FDR <0.05) in C9orf72 patient fibroblasts.\r\nConclusions: A genome wide RNA signature can be defined in fibroblasts with C9orf72 expansion. ASO-mediated reduction of C9orf72 RNA levels in fibroblasts with the hexanucleotide expansion efficiently reduced accumulation of GGGGCC RNA foci. This did not, however, generate a reversal of the C9orf72 RNA profile.
GSE51812 ImmunoHuman Arthritis 15 2 Joint injury and osteoarthritis affect millions of people worldwide, but attempts to generate articular cartilage using adult stem/progenitor cells have been unsuccessful. We hypothesized that recapitulation of the human developmental chondrogenic program using pluripotent stem cells (PSCs) may represent a superior approach for cartilage restoration. Using laser capture microdissection followed by microarray analysis, we first defined a surface phenotype (CD146low/negCD166low/negCD73+CD44lowBMPR1B+) distinguishing the earliest cartilage committed cells (pre-chondrocytes) at 5-6 weeks of development; pellet assays confirmed these cells as functional, chondrocyte-restricted progenitors. Flow cytometry, qPCR and immunohistochemistry at 17 weeks revealed that the superficial layer of peri-articular chondrocytes was enriched in cells with this surface phenotype. Isolation of cells with a similar immunophenotype from differentiating human PSCs revealed a population of CD166negBMPR1B+ putative pre-chondrocytes. Functional characterization confirmed these cells as cartilage-committed, chondrocyte progenitors. The identification of a specific molecular signature for primary cartilagecommitted progenitors may provide essential knowledge for the generation of purified, clinically relevant cartilage cells from PSCs.
GSE51869 ImmunoHuman BasicScience 11 0 Standardization of MSC manufacturing is urgently needed to facilitate comparison of clinical trial results. Here, we compare gene expression of MSC generated by the adaptation of a proprietary method for isolation and cultivation of a specific umbilical cord tissue-derived population of Mesenchymal Stromal Cells (MSCs)\r\nThe adaptation focused on different stages of production, from cell isolation steps to cell culturing and preservation. The origin and quality of reagents were considered and steps for avoiding microbiological and endotoxin contamination of the final cell product were implemented. Cell isolation efficiency, MSC surface markers and genetic profiles originating from the use of different medium supplements were compared. The ATMP-compliant UCX® product was also cryopreserved avoiding the use of DMSO, an added benefit in the use of these cells as an ATMP. Cells were analysed for expansion capacity and longevity. The final cell product was further characterised by flow cytometry, differentiation potential, and tested for contaminants at various passages. Gene expression profiles, genetic stability and immune properties were analysed.
GSE51997 ImmunoHuman SLE 36 6 This study demonstrates quantitative and qualitative differences between type I IFN signatures in autoimmunity and viral infection using purified CD4pos T cells and CD16pos- and CD16neg-monocyte subsets. We were able to discriminate between cell-specific viral response signatures and the pathogenically amplified IFN signatures observed in autoimmunity. The differences were of both a qualitative and quantitative nature, as the signatures in the patients with SLE were characterized by much more complexly compiled gene patterns with increased absolute gene expression levels.
GSE52005 ImmunoHuman 2015Q2 140 10 LAIV and TIV are effective for prevention of influenza infection in children, but the mechanisms associated with protection are still not well defined. We analyzed the differences in B cell responses and transcriptional profiles. Compared to baseline, LAIV elicited a significant increase in naïve, memory and transitional B cells on day 30, while vaccination with TIV elicited an increase in number of plasmablasts on day 7. Antibody titers against the three vaccine strains (H1N1, H3N2 and B) were significantly higher in the TIV group and correlated with number of antibody-secreting cells. Regarding transcriptional profiles, both vaccines induced expression of interferon signaling, but at different time points, TIV on 1 day, and LAIV on day 7 day post-vaccination, the last only in children younger than 5 years old. Interferon-related genes over expressed in both vaccinated groups correlated with antibody titers of H3N2 vaccines strain. These results suggest that LAIV and TIV induced significant different B cell responses in vaccinated children. Early induction on interferon genes appears important for development of effective antibody responses.
GSE52139 ImmunoHuman 2015Q2 16 1 There have been few studies that have focused on the periplaque regions surrounding demyelinated plaques, especially in spinal cords. Areas of incomplete demyelination have been demonstrated but poorly studied. The present study aimed to analyze the molecular immunopathology of periplaque demyelinated lesions (PDLs) in the spinal cord of patients with secondary progressive multiple sclerosis (MS).\r\nTo achieve this goal, the transcriptomic profiles of PDLs were analyzed in post-mortem tissues derived from the cervical spinal cord of 8 patients with primary or secondary progressive MS.
GSE52202 ImmunoHuman ALS 8 1 Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative condition characterized by loss of motor neurons in the brain and spinal cord. Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9ORF72 gene are the most common cause of the familial form of ALS (C9-ALS), as well as frontotemporal lobar degeneration and other neurological diseases. How the repeat expansion causes disease remains unclear, with both loss of function (haploinsufficiency) and gain of function (either toxic RNA or protein products) proposed. We report a cellular model of C9-ALS with motor neurons differentiated from induced pluripotent stem cells (iPSCs) derived from ALS patients carrying the C9ORF72 repeat expansion. No significant loss of C9ORF72 expression was observed, and knockdown of the transcript was not toxic to cultured human motor neurons. Transcription of the repeat was increased, leading to accumulation of GGGGCC repeat–containing RNA foci selectively in C9-ALS iPSC-derived motor neurons. Repeat-containing RNA foci colocalized with hnRNPA1 and Pur-a, suggesting that they may be able to alter RNA metabolism. C9-ALS motor neurons showed altered expression of genes involved in membrane excitability including DPP6, and demonstrated a diminished capacity to fire continuous spikes upon depolarization compared to control motor neurons. Antisense oligonucleotides targeting the C9ORF72 transcript suppressed RNA foci formation and reversed gene expression alterations in C9-ALS motor neurons. These data show that patient-derived motor neurons can be used to delineate pathogenic events in ALS.
GSE52360 ImmunoHuman ChronicInflammation 50 8 We sought to characterize delayed-type hypersensitivity (DTH) responses elicited by topical hapten DPCP in normal human skin
GSE52361 ImmunoHuman Psoriasis 12 3 Background: IL-17 is the defining cytokine of the Th17, Tc17, and ?d T cell populations that plays a critical role in mediating inflammation and autoimmunity. Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines with relevant contributions of IFN-?, TNF-a, and IL-17. Despite the pivotal role IL-17 plays in psoriasis, and in contrast to the other key mediators involved in the psoriasis cytokine cascade that are capable of inducing broad effects on keratinocytes, IL-17 was demonstrated to regulate the expression of a limited number of genes in monolayer keratinocytes cultured in vitro.\r\nMethodology/Principal Findings: Given the clinical efficacy of anti-IL-17 agents is associated with an impressive reduction in a large set of inflammatory genes, we sought a full-thickness skin model that more closely resemble in vivo epidermal architecture. Using a reconstructed human epidermis (RHE), IL-17 was able to upregulate 419 gene probes and downregulate 216 gene probes. As possible explanation for the increased gene induction in the RHE model is that CEBPß, the transcription factor regulating IL-17-responsive genes, is expressed in differentiated KCs.\r\nConclusions/Significance: The genes identified in IL-17-treated RHE are likely relevant to the IL-17 effects in psoriasis, since ixekizumab (anti-IL-17A agent) strongly suppressed the “RHE” genes in psoriasis patients treated in vivo with this IL-17 antagonist.
GSE52428 ImmunoHuman 2015Q2 649 2 Diagnosis of influenza A infection is currently based on clinical symptoms and pathogen detection. Use of host peripheral blood gene expression data to classify individuals with influenza A virus infection represents a novel approach to infection diagnosis\r\nWe used microarrays to assay peripheral blood gene expression at baseline and every 8 hours for 7 days following intranasal influenza A H1N1 or H3N2 inoculation in healthy volunteers. We determined groups of coexpressed genes that classified symptomatic influenza infection. We then tested this gene expression classifier in patients with naturally acquired respiratory illness.
GSE52463 ImmunoHuman SystemicSclerosis 15 1 Objectives: Idiopathic pulmonary fibrosis (IPF) is a complex disease in which a multitude of proteins and networks are disrupted. Interrogation of genome-wide transcription through RNA sequencing (RNA-Seq) enables the determination of genes whose differential expression is most significant in IPF, as well as the detection of alternative splicing events which are not easily observed with traditional microarray experiments.\r\nMethods: Messenger RNA extracted from 8 IPF lung samples and 7 healthy controls was sequenced on an Illumina HiSeq. Analysis of differential expression and exon usage was performed using Bioconductor packages. The gene periostin was selected for validation of alternative splicing by quantitative PCR, and pathway analysis was performed to determine enrichment for differentially expressed and spliced genes.\r\nResults: There were 873 genes differentially expressed in IPF (FDR 5%), and 440 unique genes had significant differential splicing events (FDR 5%). In particular, cassette exon 21 of the gene periostin was significantly more likely to be spliced out in IPF samples (adj pval = 2.06e-09), and this result was confirmed by qPCR (Wilcoxon pval = 3.11e-4). We also found that genes close to SNPs in the discovery set of a recent IPF GWAS were enriched for genes differentially expressed in our data, including genes like mucin5B and desmoplakin which have been previously associated with IPF.\r\nConclusions: There is significant differential splicing and expression in IPF lung samples as compared with healthy controls. We found a strong signal of differential cassette exon usage in periostin, an extracellular matrix protein whose increased gene-level expression has been associated with IPF and its clinical progression, but for which differential splicing has not been studied in the context of IPF. Our results suggest that alternative splicing of periostin and other genes may be involved in the pathogenesis of IPF.
GSE52471 ImmunoHuman Psoriasis 38 2 Discoid lupus erythematosus (DLE) is the most common skin manifestation of lupus. Despite its high frequency in systemic lupus in addition to cases without extracutaneous manifestations, targeted treatments for DLE are lacking, likely because of a dearth of knowledge of the molecular landscape of DLE skin. Here, we profiled the transcriptome of DLE skin in order to identify signaling pathways and cellular signatures that may be targeted for treatment purposes. Further comparison of the DLE transcriptome with that of psoriasis, a useful reference given our extensive knowledge of molecular pathways in this disease, provided a framework to identify potential therapeutic targets. Although a growing body of data support a role for IL-17 and T helper type 17 (Th17) cells in systemic lupus, we show a relative enrichment of IFN-?-associated genes without that for IL-17-associated genes in DLE. Extraction of T cells from the skin of DLE patients identified a predominance of IFN-?-producing Th1 cells and an absence of IL-17-producing Th17 cells, complementing the results from whole-skin transcriptomic analyses. These data therefore support investigations into treatments for DLE that target Th1 cells or the IFN-? signaling pathway.
GSE52612 ImmunoHuman PulmonaryFibrosis 8 1 Aberrant expression of master phenotype regulators by lung fibroblasts may play a central role in idiopathic pulmonary fibrosis (IPF). Interrogating IPF fibroblast transcriptome datasets, we identified Forkhead Box F1 (FOXF1), a DNA-binding protein required for lung development, as a candidate actor in IPF. Thus, we determined FOXF1 expression levels in fibroblasts cultured from normal or IPF lungs in vitro, and explored FOXF1 functions in these cells using transient and stable loss-of-function and gain-of-function models. FOXF1 mRNA and protein were expressed at higher levels in IPF compared with controls. In normal lung fibroblasts, FOXF1 repressed key fibroblast functions such as proliferation, survival, and expression of collagen-1 (COL1) and actin related protein 2/3 complex, subunit 2 (ARPC2). ARPC2 knockdown mimicked FOXF1 overexpression with regard to proliferation and COL1 expression. FOXF1 expression was induced by the antifibrotic mediator prostaglandin E2 (PGE2). Ex vivo, FOXF1 knockdown conferred CCL-210 lung fibroblasts the ability to implant and survive in uninjured mouse lungs. In IPF lung fibroblasts, FOXF1 regulated COL1 but not ARPC2 expression. In conclusion, FOXF1 functions and regulation were consistent with an antifibrotic role in lung fibroblasts. Higher FOXF1 levels in IPF fibroblasts may thus participate in a compensatory response to fibrogenesis.
GSE52742 ImmunoHuman 2015Q2 6 1 In this study we present the first genome-wide expression profiling of peripheral B cells by massive parallel RNA sequencing in patients with allergic asthma validating the discovery potential of this approach in allergy.
GSE52746 ImmunoHuman 2015Q2 39 3 Crohn's Disease (CD) is a chronic inflammatory disease of the intestinal tract.\r\nWe performed a whole-genome transcriptional analysis using colonic biopsies from CD patients before and after anti-TNF-a therapy.
GSE52778 ImmunoHuman Asthma 16 3 Rationale: Asthma is a chronic inflammatory airway disease. The most common medications used for its treatment are ß2-agonists and glucocorticosteroids, and one of the primary tissues that these drugs target in the treatment of asthma is the airway smooth muscle. We used RNA-Seq to characterize the human airway smooth muscle (HASM) transcriptome at baseline and under three asthma treatment conditions.\r\nMethods: The Illumina TruSeq assay was used to prepare 75bp paired-end libraries for HASM cells from four white male donors under four treatment conditions: 1) no treatment; 2) treatment with a ß2-agonist (i.e. Albuterol, 1µM for 18h); 3) treatment with a glucocorticosteroid (i.e. Dexamethasone (Dex), 1µM for 18h); 4) simultaneous treatment with a ß2-agonist and glucocorticoid, and the libraries were sequenced with an Illumina Hi-Seq 2000 instrument. The Tuxedo Suite Tools were used to align reads to the hg19 reference genome, assemble transcripts, and perform differential expression analysis using the protocol described in https://github.com/blancahimes/taffeta
GSE5281 ImmunoHuman AD 161 4 Information about the genes that are preferentially expressed during the course of Alzheimer’s disease (AD) could improve our understanding of the molecular mechanisms involved in the pathogenesis of this common cause of cognitive impairment in older persons, provide new opportunities in the diagnosis, early detection, and tracking of this disorder, and provide novel targets for the discovery of interventions to treat and prevent this disorder. Information about the genes that are preferentially expressed in relationship to normal neurological aging could provide new information about the molecular mechanisms that are involved in normal age-related cognitive decline and a host of age-related neurological disorders, and they could provide novel targets for the discovery of interventions to mitigate some of these deleterious effects.\r\nAim 1. Collect brain samples from three Alzheimer’s Disease Centers (ADCs) for subsequent gene expression profiling. Individuals will be stratified with respect to diagnostic groups (using both clinical and neuropathological criteria), age groups, and APOE genotype. 150 individual brains will be sampled from the Arizona ADC, the Duke University ADC, and the Washington University ADC. Miniscule sample sizes (200 um of sectioned tissue) from six brain regions that are histopathologically or metabolically relevant to AD and aging will be collected, ensuring that this proposal does not deplete the national resource. Frozen and fixed samples will be sent to Phoenix, sectioned in a standardized fashion, and then returned. Aim 2. Tissue heterogeneity will be eliminated prior to expression profiling by performing laser capture microscopy on all brain regions. Aim 3. Expression profile LCM-captured cells on the Affymetrix U133 Plus 2.0 array (~55,000 transcripts), and quickly provide these data to the community at large. Aim 4. Identify pathogenic cascades related to each of the clinico-pathologic correlates using unsupervised and supervised analyses coupled with a hypothesis-driven approach. Aim 5. Validation of the expression correlates at the protein and functional levels.\r\nScientific progress in the last few years has improved our understanding of AD and raised the hope of identifying treatments to halt the progression and prevent the onset of this disorder. For instance, researchers have begun to characterize the cascade of molecular events which lead to the major histopathological features of the disorder: neuritic plaques, which contain extra-cellular deposits of amyloid beta-peptides (Abeta); neurofibrillary tangles, which contain the hyperphosphorylated form of the intracellular, microtubule-associated protein, tau; and a loss of neurons and synapses. These molecular events provide targets for the development of promising new treatments. For example, A-beta has been postulated to trigger a cascade of events that are involved in the pathogenesis of AD. This proposal hopes to provide new information about the genes that are preferentially expressed in the development of AD histopathology, including the over-expression of APP, amyloid-induced neurotoxicity, and hyperphosphorylation of tau, as well as bring clarity to the metabolic abnormalities that seem to play a role in dementia and AD development and pathology.\r\nWe will perform LCM on 6 brain regions with about 14 biological replicates per brain region. The brain regions are as follows: 1) entorhinal cortex 2) hippocampus 3) medial temporal gyrus 4) posterior cingulate 5) superior frontal gyrus and 6) primary visual cortex. We will collect layer III pyramidal cells from the white matter in each region, isolate total RNA from LCMed cell lysates, and perform double round amplification of each sample for array analysis.
GSE52946 ImmunoHuman ALS 19 2 Amyotrophic lateral sclerosis (ALS) is a paralytic degenerative disease of the nervous system. In the SOD1 mouse model of ALS we found loss of the molecular and functional microglia signature associated with pronounced expression of miR-155 in SOD1 mice. We also found increased expression of miR-155 in the spinal cord of ALS subjects. Genetic ablation of miR-155 increased survival in SOD1 mice and reversed the abnormal microglial and monocyte molecular signature. In addition, dysregulated proteins in the spinal cord of SOD1 mice that we identified in human ALS spinal cords and CSF were restored in SOD1G93A/miR155-/- mice. Treatment of SOD1 mice with anti-miR-155 SOD1 mice injected systemically or into the cerebrospinal fluid prolonged survival and restored the microglial unique genetic and microRNA profiles. Our findings provide a new avenue for immune based therapy of ALS by targeting miR-155.
GSE53146 ImmunoHuman Vitiligo 10 1 Vitiligo skin samples with an active inflammatory infiltrate were selected for gene expression profiling in order to identify inflammatory pathways that drive depigmentation in vitiligo.
GSE53166 ImmunoHuman 2015Q2 113 2 Variation in individuals' responses to environmental factors is believed to influence susceptibility to complex diseases in humans. The genetic basis of such variation is poorly understood. We measured gene expression from resting and stimulated dendritic cells (DCs) derived from the peripheral blood of healthy individuals. We stimulated the primary DCs with E. coli lipopolysaccharide (LPS) or influenza virus. Using serial replicate samples, we selected genes that showed evidence of reproducibility within the serial replicates.
GSE53306 ImmunoHuman 2015Q2 40 3 Our objective was to elucidate patterns of gene expression underlying the progression of UC disease.\r\nSingle endoscopic pinch biopsies (n=40) were assayed using the Illumina cDNA-mediated Annealing, Selection, Extension, and Ligation (DASL) microarray. Tissue was sampled in consecutive active and quiescent stages at the same site in individual UC patients, and these stages (active and inactive) were compared with each other as well as to non-inflammatory bowel disease (non-IBD) healthy controls.
GSE53431 ImmunoHuman Psoriasis 47 3 Psoriasis is a common chronic inflammatory and hyperproliferative immune-mediated skin disorder. Narrow-band UVB (NB-UVB) phototherapy is a convenient first-line treatment of psoriasis, though the mechanisms underlying its efficacy have not been completely elucidated. In order to improve our understanding of NB-UVB phototherapy, gene expression profiling was used to characterize gene expression in lesional epidermis from psoriasis patients undergoing NB-UVB phototherapy. Increased expression of melanogenesis pathway genes was observed to be the earliest response. At the end of treatment, genes involved in diverse biological processes were affected, such as pigmentation, cell adhesion, ectodermal development and metabolism. The relationship between gene expression and treatment outcome was further studied using Partial Least Squares Discriminant Analysis (PLS-DA). Gene ontology analysis showed that genes responding to phototherapy and highly correlated to treatment outcome were involved in oxidation reduction, growth and mitochondria organization. In particular SPATA18, a key regulator of mitochondria quality, was found to be significantly downregulated in psoriasis, and its upregulation following phototherapy was required for optimal clinical improvement. Our data suggest that oxidation reduction is a critical event for the resolution of psoriatic plaques.
GSE53514 ImmunoHuman BasicScience 36 5 CD4(+) type 1 T regulatory (Tr1) cells are induced in the periphery and have a pivotal role in promoting and maintaining tolerance. The absence of surface markers that uniquely identify Tr1 cells has limited their study and clinical applications. By gene expression profiling of human Tr1 cell clones, we identified the surface markers CD49b and lymphocyte activation gene 3 (LAG-3) as being stably and selectively coexpressed on mouse and human Tr1 cells. We showed the specificity of these markers in mouse models of intestinal inflammation and helminth infection and in the peripheral blood of healthy volunteers. The coexpression of CD49b and LAG-3 enables the isolation of highly suppressive human Tr1 cells from in vitro anergized cultures and allows the tracking of Tr1 cells in the peripheral blood of subjects who developed tolerance after allogeneic hematopoietic stem cell transplantation. The use of these markers makes it feasible to track Tr1 cells in vivo and purify Tr1 cells for cell therapy to induce or restore tolerance in subjects with immune-mediated diseases.
GSE53543 ImmunoHuman COPD 196 1 Rhinovirus (RV) is the most prevalent human respiratory virus. Each year, RV infects billions of people and is responsible for at least half of all common colds, the most common illness of humans. RV infection also affects the morbidity of a range of respiratory illnesses, such as bronchiolitis, pneumonia, asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Despite its biological importance and public health significance, little is known about the genetic architecture of response to RV. To address this, we obtained genome-wide genotype and gene expression data in uninfected and RV-infected peripheral blood mononuclear cells (PBMCs) from 98 individuals. We characterized gene expression differences in response to RV infection and mapped expression quantitative trait loci (eQTLs) in both uninfected and RV-infected PBMCs.
GSE53552 ImmunoHuman Psoriasis 99 4 To explore the psoriasis phenotype and pathways involved in psoriasis, we characterized gene expression in lesional and non-lesional skin from psoriasis patients. Furthermore, we explored the effects of various doses of brodalumab on lesional skin over time.
GSE53716 ImmunoHuman 2015Q2 12 1 IFNb has been used as a first line therapy for relapsing remitting multiple sclerosis (RRMS). Since only a few studies have addressed the role of endogenous IFNb in the pathogenesis of the disease, our objective was to characterize its role in the transcriptional regulation of pathogenic Th17 cytokines in patients with RRMS. In-vitro studies have demonstrated that IFNb inhibited IL-17A, IL-17F, IL-21, IL-22 and IFN-b secretion in CD4+ lymphocytes through the induction of suppressor of cytokine secretion (SOCS)1 and 3. We found that patients with RRMS have increased serum and cerebrospinal fluid (CSF) Th17 (IL-17A and IL-17F) cytokine levels in comparison to the control subjects, suggesting that deficient endogenous IFNbeta secretion and/or signaling may contribute to the dysregulation of those pathogenic cytokines in CD4+ cells. We identified that the endogenous IFNb from serum of RRMS patients induced a significantly lower IFN-inducible gene expression in comparison to healthy controls (HCs). In addition, in-vitro studies have revealed a deficient endogenous and exogenous IFNb signaling in CD4+ cells derived from MS patients. Interestingly, upon inhibition of the endogenous IFNb signaling by silencing interferon regulatory factor (IRF)7 gene expression, the resting CD4+ T cells secreted significantly higher level of IL-17A, IL-17F, IL-21, IL-22 and IL-9, suggesting that endogenous IFNb suppresses the secretion of these pathogenic cytokines. In-vivo recombinant IFNb-1a treatment induced IFNAR1 and its downstream signaling molecules’ gene expression, suggesting that treatment may reconstitute a deficient endogenous IFNbeta regulation of the CD4+ T-cells’ pathogenic cytokine production in MS patients.
GSE53751 ImmunoHuman Psoriasis 12 5 To understand the role of epidermal keratinocytes in immunopathology of skin diseases with predominant T helper (Th) cell responses, we measured the genome-wide transcriptional profile of human keratinocytes in response to IFNgamma, IL-4, IL-17A or IL-22, major cytokines produced by Th1, Th2, Th17 or Th22 cells, respectively.\r\nIL-6 was also included in the transcriptional profile analysis because a variety of pro-inflammatory stimuli stimulate human keratinocytes to produce IL-6 that has an autocrine or paracrine role in epidermal immunity.
GSE53890 ImmunoHuman AD 41 3 Comparison of the gene expression profiles of adult human brain samples from frontal cortical regions, including samples from young, middle aged, normal aged.
GSE54017 ImmunoHuman NormalControl 8 1 Antibody-independent effector functions of B cells, such as antigen presentation and cytokine production, have been shown to play an important role in a variety of immune-mediated conditions such as autoimmune diseases, transplant rejection and graft-versus-host disease. Therapeutic strategies, which interfere with B cell activation could therefore be a useful addition to the current immunosuppressive armamentarium. CD40 is one of the strongest activation stimuli for B cells. The aim of this study was to characterise the gene expression changes that occurr after B cell activation via CD40.
GSE54293 ImmunoHuman Influenza 8 3 The influenza A(H1N1)pdm09 virus caused a global flu pandemic in 2009 and contributes to seasonal epidemics. Different treatment and prevention options for influenza have been developed and applied with limited success. Here we report that an Akt inhibitor MK2206 possesses potent antiviral activity against influenza A(H1N1)pdm09 virus in vitro. We showed that MK2206 blocks the entry of different A(H1N1)pdm09 strains into cells. Moreover, MK2206 prevented A(H1N1)pdm09-mediated activation of cellular signaling pathways and the development of cellular immune responses. Importantly, A(H1N1)pdm09 virus was unable to develop resistance to MK2206. Thus, MK2206 is a potent anti-influenza A(H1N1)pdm09 agent.
GSE54409 ImmunoHuman ALS 5 1 Although many distinct mutations in a variety of genes are known to cause Amyotrophic Lateral Sclerosis (ALS), it remains poorly understood how they selectively impact motor neuron biology and whether they converge on common pathways to cause neural degeneration. Here, we have combined reprogramming and stem cell differentiation approaches with genome engineering and RNA sequencing to define the transcriptional changes that are induced in human motor neurons by mutant SOD1. Mutant SOD1 protein induced a transcriptional signature indicative of increased oxidative stress, reduced mitochondrial function, altered sub-cellular transport as well as activation of the ER stress and unfolded protein response pathways. Functional studies demonstrated that perturbations in these pathways were indeed the source of altered transcript levels.
GSE54456 ImmunoHuman 2015Q2 174 1 To increase our understanding of psoriasis, we utilized RNA-seq to assay the transcriptomes of lesional psoriatic and normal skin. We sequenced polyadenylated RNA-derived cDNAs from 92 psoriatic and 82 normal punch biopsies, generating an average of ~38 million single-end 80-bp reads per sample. Comparison of 42 samples* examined by both RNA-seq and microarray [GSE13355] revealed marked differences in sensitivity, with transcripts identified only by RNA-seq having much lower expression than those also identified by microarray. RNA-seq identified many more differentially expressed transcripts enriched in immune system processes. Weighted gene co-expression network analysis (WGCNA) revealed multiple modules of coordinately expressed epidermal differentiation genes, overlapping significantly with genes regulated by the long non-coding RNA TINCR, its target gene, staufen-1 (STAU1), the p63 target gene ZNF750, and its target KLF4. Other coordinately expressed modules were enriched for lymphoid and/or myeloid signature transcripts and genes induced by IL-17 in keratinocytes. Dermally-expressed genes were significantly down-regulated in psoriatic biopsies, most likely due to expansion of the epidermal compartment. These results demonstrate the power of WGCNA to elucidate gene regulatory circuits in psoriasis, and emphasize the influence of tissue architecture in both differential expression and co-expression analysis.\r\n*The list of 42 samples examined by both RNA-seq and microarray is provided in the 'MAoverlappedsamples.txt'.
GSE5450 ImmunoHuman PulmonaryFibrosis 6 2 Idiopathic pulmonary fibrosis (IPF) is a refractory and lethal interstitial lung disease characterized by alveolar epithelial cells apoptosis, fibroblast proliferation and extra-cellular matrix proteins deposition. Epstein - Barr virus (EBV) has previously been localised to alveolar epithelial cells of IPF patients. In this study we utilised a microarray based differential gene expression analysis strategy to identify potential molecular drivers of EBV associated lung fibrosis. We employed an alveolar epithelial cell line infected with EBV (A-Akata). Lytic phase infection induced in the A-Akata cells by TPA/BA treatment resulted in increase of TGFbeta1 and TIEG1 mRNA expression. Treatment of the A-Akata cells with ganciclovir,\r\nresulted in a down regulation of both TIEG1 and TGFbeta1 expression, accompanied by a suppression of the EBV early response genes, Rta and Zta. This suppression of cell turnover mediators was correlated with an increase in cell activity index. To identify a possible role for Rta in driving apoptotic gene expression, we inhibited the Rta gene expression by silencing RNA, resulting in a decrease in TGFbeta1 and TIEG1 expression. This study identifies an apoptotic role of the EBV early response genes, as enhancer factors of TIEG1 and TGFbeta1 in EBV infected alveolar epithelial cells, potentially providing a possible mechanism for the role of EBV infection in pulmonary fibrosis.
GSE54522 ImmunoHuman 2015Q2 46 20 Analysis of gene-expression profiles with microarrays can be very useful to dissect specific responses and to characterize with a global view, new elements for improving the diagnosis, treatment and understanding of allergic diseases. We have used this approach for studying the olive pollen response, taking advantage our previous results of T-cell epitope mapping on Ole e 1 molecule (the major allergen from olive pollen) in order to analyze the stimuli influence on the gene-expression of olive pollen allergic patients. Peripheral blood mononuclear cells (PBMCs) from 6 healthy controls and 6 allergic subjects were stimulated 24 hours with olive pollen stimuli: Ole e 1 molecule and two Ole e 1 peptides previously defined as P2+3 (aa10-31), mainly recognized by non-allergic subjects (possible immunoregulatory epitope) and P10+12+13 (aa90-130), immunodominant T-cell epitope. RNA extracted from basal and stimulated PBMCs was analyzed by HuGeU133 plus 2.0 GeneChip, Affymetrix (38.500genes). After assessment of data quality by standard quality checks and principal components analysis (PCA), differential gene-expression by experimental conditions was performed by multiple testing, using microarrays specific software. Differences in functional analysis were performed by KEGG, for pathways and Gene-Ontology for biological process. The results of gene-expression by PCA showed differential clusters that correlated with the experimental conditions from samples of allergic patients. Analysis of differential gene-expression by multiple testing, and functional analysis by KEGG and Gene-Ontology revealed differential genes and pathways among the 4 experimental conditions.
GSE5457 ImmunoHuman PulmonaryFibrosis 8 2 Idiopathic pulmonary fibrosis (IPF) is a refractory and lethal interstitial lung disease; EBV has previously been localised to alveolar epithelial cells of IPF patients. The molecular process of the epithelial mesenchymal transition (EMT) in IPF remains still unknown. Using an oligonucleotide array analysis, we observed dysregulated expression of members of non-canonical Wnt family in EBV infected A549 after TGF?1 exposure. TGF?1 exposure induced EMT increasing ?-Smooth Muscle Actin (ACTC) and Wnt5b gene expression, but decreasing E-cadherin and DKK1. When data were analyzed as a function of Wnt5b in EMT, significance differences in ACTC and E-cadherin gene expression, active TGF?1 protein levels and collagen deposition could be detected. Treatment with 9-cis Retinoic Acid (9-cisRA) significantly inhibited Wnt5b expression in both EBV infected and non-infected A549, followed by decreased collagen deposition and active TGF?1 protein level. Specific non-canonical Wnt-signalling genes are dysregulated in EBV infected cells and A549 treated with TGF?1; while, 9-cisRA treatment appears to attenuate EMT process in vitro.
GSE54629 ImmunoHuman 2015Q2 138 7 Objective: We performed whole-blood transcriptomic profiling for patients with rheumatoid arthritis (RA) who received rituximab (RTX). We aimed to identify a molecular signature that could predict the clinical response to RTX and transcriptomic changes after RTX therapy.
GSE54837 ImmunoHuman COPD 226 3 Investigation of gene expression profiles among patients with COPD frequent exacerbations and to find gene targets as predictors of exacerbations
GSE54884 ImmunoHuman Psoriasis 6 1 The levels of IL-17 are elevated in the serum of psoriasis patients. However, the effects of IL-17 on circulating leukocytes bearing the IL-17 receptors are not fully understood. Of particular interest are monocytes, as the activation and recruitment of effector monocytes underlies the pathobiology of a number systemic inflammatory diseases, including psoriasis co-morbidities, such as atherosclerosis, metabolic regulation in adipose tissue and psoriatic arthritis. Human monocytes highly express both IL-17RA and IL-17RC and chemotraffick in response to IL-17. We explored the impact of IL-17 on blood monocytes. Using cDNA microarray, , we molecularly characterized how human blood monocytes respond to IL-17A in vitro.
GSE54953 ImmunoHuman BasicScience 8 2 Owing to their manifold immune regulatory functions, regulatory T cells (Treg) have received tremendous interests as targets for therapeutic intervention of diverse immunological pathologies or cancer. Directed manipulation of Treg will only be achievable with extensive knowledge about the intrinsic programs that define their regulatory function. We simultaneously analyzed miR and mRNA transcript levels in resting and activated human Treg cells in comparison to non-regulatory conventional T cells (Tcon). Based on experimentally validated miR-target information, both transcript levels were integrated into a comprehensive pathway analysis. This strategy revealed characteristic signal transduction pathways involved in Treg biology such as TCR-, TLR-, TGF?-, JAK/STAT- and mTOR signaling and allowed for the prediction of specific pathway activities on the basis of miR and mRNA transcript levels in a probabilistic manner. These data encourage new concepts for targeted control of Treg cell effector function.
GSE55036 ImmunoHuman SystemicSclerosis 53 3 Systemic sclerosis is associated with skin fibrosis thought mediated by TGFb. This open label clinical trial examines the effect of TGFb inhibition on skin gene expression.\r\nPatients 1-9 received two doses 1 mg/kg dose of fresolimumab at baseline and 3 weeks; patients 10-19 received a single 5 mg/kg dose
GSE55201 ImmunoHuman Psoriasis 81 2 The effect of anti-IL-17 treatment on systemic inflammation is not fully understand. Using cDNA microarray, genomic analysis methods such as GSEA and ingenuity, we characterized the transcriptional changes in the blood of psoriasis patients afer systemic neutralization of IL-17 compared to baseline (before treatment). We also compared the whole blood-derived transcriptome between psoraisis patients at baseline and healthy volunteers to examine systemic inflammation in psoriasis patients.
GSE55235 ImmunoHuman Arthritis 30 3 Discrimination of rheumatoid arthritis (RA) patients from patients with other inflammatory/degenerative joint diseases or healthy individuals purely on the basis of genes differentially expressed in high-throughput data has proven very difficult. Thus, the present study sought to achieve such discrimination by employing a novel unbiased approach using rule-based classifiers. Three multi-center genome-wide transcriptomic data sets (Affymetrix HG- U133 A/B) from a total of 79 individuals, including 20 healthy controls (control group - CG), as well as 26 osteoarthritis (OA) and 33 RA patients, were used to infer rule- based classifiers to discriminate the disease groups. The rules were ranked with respect to Kiendl’s statistical relevance index, and the resulting rule set was optimized by pruning. The rule sets were inferred separately from data of one of three centers and applied to the two remaining centers for validation. All rules from the optimized rule sets of all centers were used to analyze their biological relevance applying the software Pathway Studio.\r\nThe optimized rule sets for the three centers contained a total of 29, 20, and 8 rules (including 10, 8, and 4 rules for ‘RA’), respectively. The mean sensitivity for the prediction of RA based on six center-to-center tests was 96% (range 90% to 100%), that for OA 86% (range 40% to 100%). The mean specificity for RA prediction was 94% (range 80% to 100%), that for OA 96% (range 83.3% to 100%). The average overall accuracy of the three different rule-based classifiers was 91% (range 80% to 100%). Unbiased analyses by Pathway Studio of the gene sets obtained by discrimination of RA from OA and CG with rule-based classifiers resulted in the identification of the pathogenetically and/or therapeutically relevant interferon-gamma and GM-CSF pathways.\r\nFirst-time application of rule-based classifiers for the discrimination of RA resulted in high performance, with means for all assessment parameters close to or higher than 90%. In addition, this unbiased, new approach resulted in the identification not only of pathways known to be critical to RA, but also of novel molecules such as serine/threonine kinase 10.
GSE55319 ImmunoHuman Arthritis 112 2 To determine whether gene expression profiles from peripheral whole blood could be used to determine therapeutic outcome in a cohort of children with newly diagnosed polyarticular JIA.
GSE55447 ImmunoHuman SLE 208 6 Background/Purpose: Systemic lupus erythematosus (SLE) is a complex multi-system autoimmune disease of uncertain etiology. Patients from different ancestral backgrounds demonstrate differences in clinical manifestations and autoantibody profiles. In this study we examined genome-wide transcriptional patterns in major immune cell subsets across different ancestral backgrounds.\r\nMethods: Peripheral blood was collected from 21 African-American (AA) and 21 European-American (EA) SLE patients, 5 AA controls, and 5 EA controls. CD4+ T-cells, CD8+ T-cells, monocytes and B cells were purified by flow sorting. Each cell subset from each subject was run on an Illumina HumanHT-12 V4 expression BeadChip array (n=208 arrays). Differentially expressed genes (DEGs) were determined by comparing cases and controls of the same ancestral background.\r\nResults: The overlap in DEG lists between different cell types from the same ancestral background was very modest (<1%). Typically between 5-10% of DEGs were shared when comparing the same cell type between different ancestral backgrounds (for ex. CD20 AA vs. CD20 EA). Quantitative measurement of global IFN-stimulated gene (ISG) expression revealed that AA subjects demonstrated more concordance across all studied cell types. Two subgroups of patients were identified based on the ISG expression profiles. One subgroup showed higher ISGs expression in all cell types, and the other subgroup had higherISG expression only in T and B lymphocytes but not in monocytes. The correlation of ISG expression with medication data revealed that only the B cells had lower ISG expression in patients taking immunosuppressants, while ISG expression in the other cell types did not differ based upon medication use.\r\nConclusion: We find striking differences in gene expression between different immune cell subsets and between ancestral backgrounds in SLE patients. The IFN signature is diverse, with different transcripts represented in different cell populations, and signature-positive cell subsets differed in EA vs. AA patients. We also find that treatment with the immunosuppressive agents correlates with the down-regulation of B cell ISG expression, and this was not observed in other cell types.
GSE55457 ImmunoHuman Arthritis 33 2 Discrimination of rheumatoid arthritis (RA) patients from patients with other inflammatory/degenerative joint diseases or healthy individuals purely on the basis of genes differentially expressed in high-throughput data has proven very difficult. Thus, the present study sought to achieve such discrimination by employing a novel unbiased approach using rule-based classifiers. Three multi-center genome-wide transcriptomic data sets (Affymetrix HG- U133 A/B) from a total of 79 individuals, including 20 healthy controls (control group - CG), as well as 26 osteoarthritis (OA) and 33 RA patients, were used to infer rule- based classifiers to discriminate the disease groups. The rules were ranked with respect to Kiendl’s statistical relevance index, and the resulting rule set was optimized by pruning. The rule sets were inferred separately from data of one of three centers and applied to the two remaining centers for validation. All rules from the optimized rule sets of all centers were used to analyze their biological relevance applying the software Pathway Studio.\r\nThe optimized rule sets for the three centers contained a total of 29, 20, and 8 rules (including 10, 8, and 4 rules for ‘RA’), respectively. The mean sensitivity for the prediction of RA based on six center-to-center tests was 96% (range 90% to 100%), that for OA 86% (range 40% to 100%). The mean specificity for RA prediction was 94% (range 80% to 100%), that for OA 96% (range 83.3% to 100%). The average overall accuracy of the three different rule-based classifiers was 91% (range 80% to 100%). Unbiased analyses by Pathway Studio of the gene sets obtained by discrimination of RA from OA and CG with rule-based classifiers resulted in the identification of the pathogenetically and/or therapeutically relevant interferon-gamma and GM-CSF pathways. First-time application of rule-based classifiers for the discrimination of RA resulted in high performance, with means for all assessment parameters close to or higher than 90%. In addition, this unbiased, new approach resulted in the identification not only of pathways known to be critical to RA, but also of novel molecules such as serine/threonine kinase 10.
GSE55468 ImmunoHuman Arthritis 26 0 Analysis of the regulatory architecture of gene expression variation in CD4+ T cells from patients with active RA. We have integrated gene expression with genotyping data in order to identify eQTLs that characterize the gene expression of CD4+ T cells in active RA.
GSE55584 ImmunoHuman Arthritis 16 1 Discrimination of rheumatoid arthritis (RA) patients from patients with other inflammatory/degenerative joint diseases or healthy individuals purely on the basis of genes differentially expressed in high-throughput data has proven very difficult. Thus, the present study sought to achieve such discrimination by employing a novel unbiased approach using rule-based classifiers. Three multi-center genome-wide transcriptomic data sets (Affymetrix HG- U133 A/B) from a total of 79 individuals, including 20 healthy controls (control group - CG), as well as 26 osteoarthritis (OA) and 33 RA patients, were used to infer rule- based classifiers to discriminate the disease groups. The rules were ranked with respect to Kiendl’s statistical relevance index, and the resulting rule set was optimized by pruning. The rule sets were inferred separately from data of one of three centers and applied to the two remaining centers for validation. All rules from the optimized rule sets of all centers were used to analyze their biological relevance applying the software Pathway Studio. The optimized rule sets for the three centers contained a total of 29, 20, and 8 rules (including 10, 8, and 4 rules for ‘RA’), respectively. The mean sensitivity for the prediction of RA based on six center-to-center tests was 96% (range 90% to 100%), that for OA 86% (range 40% to 100%). The mean specificity for RA prediction was 94% (range 80% to 100%), that for OA 96% (range 83.3% to 100%). The average overall accuracy of the three different rule-based classifiers was 91% (range 80% to 100%). Unbiased analyses by Pathway Studio of the gene sets obtained by discrimination of RA from OA and CG with rule-based classifiers resulted in the identification of the pathogenetically and/or therapeutically relevant interferon-gamma and GM-CSF pathways. First-time application of rule-based classifiers for the discrimination of RA resulted in high performance, with means for all assessment parameters close to or higher than 90%. In addition, this unbiased, new approach resulted in the identification not only of pathways known to be critical to RA, but also of novel molecules such as serine/threonine kinase 10.
GSE55962 ImmunoHuman COPD 106 4 We analyzed total leukocyte gene expression using Affymetrix microarrays from healthy smokers, COPD patients and non-smoking control subjects before and after exposure to acute cigarette smoke (smoking two cigarettes in 30 minutes).
GSE56341 ImmunoHuman COPD 22 1 Gene expression profiles in this submission were part of an integrative DNA methylation and gene expression integrative study. The goal of this study was to determine whether DNA methylation patterns were disrupted in small airway epithelia of patients with Chronic Obstructive Pulmonary Disease (COPD) compared to airways from subjects with normal lung function. No subject has cancer or asthma at time of collection. Corresponding DNA methylation profiles for these subjects can be found at GSE55454.\r\nWe concluded that methylation alterations in COPD airways may underlie disease-specific gene-expression changes (such as the Nrf2 oxidative response pathway).
GSE56342 ImmunoHuman COPD 22 1 This SuperSeries is composed of the SubSeries listed below.
GSE56396 ImmunoHuman nomodel 112 0 Evaluation of the airway transcriptome may reveal patterns of gene expression that are associated with clinical phenotypes of asthma. To define transcriptomic endotypes of asthma (TEA) we analyzed gene expression in induced sputum that correlate with phenotypes of disease. Gene expression was measured in sputum of subjects with asthma using Affymetrix HuGene ST 1.0 microarrays. Unsupervised clustering analysis of genes identified TEA clusters. Clinical characteristics were compared.
GSE56409 ImmunoHuman Arthritis 102 6 Synovial fibroblasts in persistent inflammatory arthritis have been suggested to have parallels with cancer growth and wound healing, both of which involve a stereotypical serum response program. We tested the hypothesis that a serum response program can be used to classify diseased tissues, and investigated the serum response program in fibroblasts from multiple anatomical sites and two diseases. To test our hypothesis we utilized a bioinformatics approach to explore a publicly available microarray dataset including RA, OA and normal synovial tissue, then extended those findings in a new microarray dataset representing matched synovial, bone marrow and skin fibroblasts cultured from RA and OA patients undergoing arthroplasty. The classical fibroblast serum response program discretely classified RA, OA and normal synovial tissues. Analysis of low and high serum treated fibroblast microarray data revealed a hierarchy of control, with anatomical site the most powerful classifier followed by response to serum and then disease. In contrast to skin and bone marrow fibroblasts, exposure of synovial fibroblasts to serum led to convergence of RA and OA expression profiles. Pathway analysis revealed three inter-linked gene networks characterising OA synovial fibroblasts: Cell remodelling through insulin-like growth factors, differentiation and angiogenesis through ß3 integrin, and regulation of apoptosis through CD44. We have demonstrated that Fibroblast serum response signatures define disease at the tissue level, and that an OA specific, serum dependent repression of genes involved in cell adhesion, extracellular matrix remodelling and apoptosis is a critical discriminator between cultured OA and RA synovial fibroblasts.
GSE56448 ImmunoHuman IBD 8 1 Resident human lamina propria immune cells serve as powerful effectors in host defense. Molecular events associated with the initiation of an intestinal inflammatory response in these cells are largely unknown. Here, we aimed to characterize phenotypic and functional changes induced in these cells at the onset of intestinal inflammation using a human intestinal organ culture model. In this model, healthy human colonic mucosa was depleted of epithelial cells by EDTA treatment. Following loss of the epithelial layer, expression of the inflammatory mediators IL-1ß, IL-6, IL-8, IL-23p19, TNF-a, CXCL2 and the surface receptors CD14, TLR2, CD86, CD54 was rapidly induced in resident lamina propria cells in situ as determined by qRT-PCR and immunohistology. Gene microarray analysis of lamina propria cells obtained by laser-capture microdissection provided an overview of global changes in gene expression occurring during the initiation of an intestinal inflammatory response in these cells. Bioinformatic analysis gave insight into signalling pathways mediating this inflammatory response. Furthermore, comparison with published microarray datasets of inflamed mucosa in vivo (ulcerative colitis) revealed a significant overlap of differentially regulated genes underlining the in vivo relevance of the organ culture model. The organ culture model characterized may be useful to study molecular mechanisms underlying the initiation of an intestinal inflammatory response in normal mucosa as well as potential alterations of this response in inflammatory bowel disease.
GSE56681 ImmunoHuman Arthritis 19 4 The alarmins myeloid-related protein (MRP) 8 and MRP14 are the dominant cytoplasmic proteins in phagocytes. After release by activated phagocytes extracellular MRP8/MRP14 complexes promote inflammation in many diseases, including infections, allergies, autoimmune diseases, rheumatoid arthritis or inflammatory bowel disease. As receptors for the pro-inflammatory effects of human MRP8, the active component of the MRP8/MRP14-complex, Toll-like receptor (TLR) 4 and the multi-ligand receptor of advanced glycation end products (RAGE) are controversial discussed. Using a comparative bioinformatics analysis between genome-wide response patterns of monocytes to MRP8, endotoxin and different cytokines we demonstrated a dominant role of TLR4 during MRP8-mediated phagocyte activation. The relevance of this signaling pathway could be confirmed in independent cell models for TLR4 and RAGE dependent signaling in mouse and man. In addition to well-known proinflammatory functions of MRP8 our systems biology approach unraveled a novel anti-apoptotic effect of MRP8 on monocytes which was confirmed in independent functional experiments. Our data define the dominance of the TLR4-MRP8 axis in activation of human phagocytes which represents a novel attractive target for modulation of overwhelming innate immune responses.\r\nWe used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated genes during this process.
GSE56789 ImmunoHuman IBD 40 0 Genome wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with diseases of the colon including inflammatory bowel diseases (IBD) and colorectal cancer (CRC). However, the functional role of many of these SNPs is largely unknown and tissue-specific resources are lacking. Expression quantitative trait loci (eQTL) mapping identifies target genes of disease-associated SNPs. Here, we comprehensively map eQTLs in the human colon, assess their relevance for GWAS of colonic diseases and provide functional characterization.
GSE56808 ImmunoHuman ALS 18 2 Amyotrophic lateral sclerosis and primary lateral sclerosis are two syndromic variants within the motor neurone disease spectrum. Whilst primary lateral sclerosis is associated with loss of upper motor neurons and a more benign disease course up to 17yrs, amyotrophic lateral sclerosis is caused by loss of both upper and lower motor neurons and has an average disease course of 2-3 years. The majority of cases are sporadic, thereby limiting the availability of cellular models for investigating pathogenic disease mechanisms.\r\nThe aim of the present study was to evaluate fibroblasts as a cellular model for sporadic amyotrophic lateral sclerosis and primary lateral sclerosis, to establish whether disease-related dysregulated biological processes recapitulate those seen in the central nervous system and to elucidate pathways that distinguish between the two disease phenotypes.
GSE57148 ImmunoHuman 2015Q2 189 1 We analyzed gene expression profiling of lung tissue to define molecular pathway of COPD using recent RNA sequencing technology.Lung tissue was obtained from 98 COPD subjects and 91 subjects with normal spirometry. RNA isolated from these samples was processed with RNA-seq using HiSeq 2000. Gene expression measurements were calculated using Cufflinks software. Differentially expressed genes and isoforms were chosen using t-test. Some of differentially expressed genes were validated by quantitative real-time PCR.
GSE57183 ImmunoHuman Arthritis 14 2 Biomarker identification for diagnosis of systemic juvenile idiopathic arthritis (SJIA), an auto-inflammatory disease that presents with prolonged fevers.
GSE57225 ImmunoHuman Psoriasis 62 2 Comparing molecular signatures of psoriasis and eczema in patients co-affected by both diseases provides a comprehensive understanding of disease pathogenesis as well as a diagnostic tool to differentiate these widespread inflammatory skin diseases.
GSE57376 ImmunoHuman 2015Q2 32 4 Object: to understand Infliximab treatment effect on the molecular expression of tissue at disease site
GSE57383 ImmunoHuman 2015Q2 112 9 objection: The immune inflammatory disorders rheumatoid arthritis (RA), psoriatic arthritis (PsA) and psoriasis (Ps) share common pathologic features and show responsiveness to anti-tumor necrosis factor (TNF) agents yet they are phenotypically distinct. The aim of this study was to examine if anti-TNF therapy is associated with divergent gene expression profiles in circulating cells and target tissues of patients with these diseases\r\nMethod: Peripheral blood CD14+ and CD14- cells were isolated from 9 RA, 12 PsA and 10 Ps patients before and after infliximab (IFX) treatment
GSE57386 ImmunoHuman nomodel 255 0 This SuperSeries is composed of the SubSeries listed below.
GSE57405 ImmunoHuman 2015Q2 111 9 objection: The immune inflammatory disorders rheumatoid arthritis (RA), psoriatic arthritis (PsA) and psoriasis (Ps) share common pathologic features and show responsiveness to anti-tumor necrosis factor (TNF) agents yet they are phenotypically distinct. The aim of this study was to examine if anti-TNF therapy is associated with divergent gene expression profiles in circulating cells and target tissues of patients with these diseases\r\nMethod: Peripheral blood CD14+ and CD14- cells were isolated from 9 RA, 12 PsA and 10 Ps patients before and after infliximab (IFX) treatment.
GSE57475 ImmunoHuman PD 142 1 Importance. Biological markers of Parkinson’s disease are essential for achieving disease modification. Objective. To determine the association of SNCA blood transcript levels with prevalence of Parkinson’s disease. Background. The SNCA locus is preferentially transcribed in neurons and blood cells. Non-coding genetic variants and neuronal aggregates of a-synuclein protein associate this locus with sporadic Parkinson’s disease and suggest a potential role for abnormal SNCA transcription in the disease mechanism. Here we investigated variation in intracellular SNCA gene expression and SNCA transcript isoform abundance in circulating blood cells of cases with PD and controls in a network of biobanks that represent regional, national, and international populations. Design, Setting, Participants. Three cross-sectional, case-control studies nested in observational biomarker studies. 222 cases with early-stage clinical PD and 183 controls were enrolled from 2005 to 2010 in the Harvard Biomarker Study (HBS) at two Harvard-affiliated tertiary care centers. 76 cases with dopamine transporter imaging (DAT)-confirmed PD and 42 controls were enrolled between August 2007 and December 2008 in the Blood a-Synuclein, Gene Expression and Smell Testing as Diagnostic and Prognostic Biomarkers in Parkinson’s Disease Study (PROBE) study from 22 US tertiary care centers. 202 DAT-confirmed cases with de novo PD and 138 controls were enrolled in the Parkinson’s Progression Markers Initiative (PPMI) between July 2010 and November 2012 from 22 US and international tertiary care centers. Main Outcome Measures. Association of intracellular SNCA transcript abundance with PD estimated on analog and digital expression platforms. Results. Reduced levels of SNCA transcripts were associated with early-stage clinical PD, neuroimaging-confirmed PD, and untreated, neuroimaging-confirmed PD in accessible, peripheral blood cells from a total of 863 individuals. SNCA expression was reduced by 17%, 22%, and 16% in cases compared to controls in the HBS, PROBE, and PPMI study with P values of 0.004, 0.025, and 0.018, respectively, after adjusting for clinical, hematological, and processing covariates. Specific SNCA transcripts with long 3’ untranslated regions (UTR) and those skipping exon 5 are implicated in the accumulation and mitochondrial targeting of a-synuclein protein in Parkinson’s pathology. These transcript isoforms were linked to PD through digital expression analysis. Individuals in the lowest quartile of SNCA expression values had covariate-adjusted odds ratios for PD of 2.14 (95% C. I. 1.1-4.1), 4.5 (95% C. I. 1.3-15), and 2.1 (1.1-4.0) compared to individuals in the highest quartile of expression values in the HBS, PROBE, and PPMI study, respectively. Conclusions and Relevance. Reduced levels of SNCA expression, particularly of disease-relevant transcripts with extended 3’ UTR or exon 5 skipping, are associated with early-stage PD. These findings support a potential role for SNCA as a transcriptional marker of PD and may have implications for patient stratification and risk assessment.
GSE57723 ImmunoHuman 2015Q2 4 1 Here we explored how the human macrophage response to tumor necrosis factor (TNF) is regulated by human synovial fibroblasts, the representative stromal cell type in the synovial lining of joints that become activated during inflammatory arthritis. Genome-wide transcriptome analysis (RNAseq) showed that co-cultured synovial fibroblasts modulate the expression of approximately one third of TNF-inducible genes in macrophages, including expression of target genes in pathways important for macrophage survival and polarization towards an alternatively activated phenotype. This work furthers our understanding of the interplay between innate immune and stromal cells during an inflammatory response, one that is particularly relevant to inflammatory arthritis. Our findings also identify modulation of macrophage phenotype as a new function for synovial fibroblasts that may prove to be a contributing factor in arthritis pathogenesis.
GSE57945 ImmunoHuman 2015Q2 315 2 We report the global pattern of ileal gene expression in a cohort of 359 treatment-naïve pediatric Crohn Disease, Ulcerative Colitis patients and controls. We focus on genes with consistent altered expression in inflamed and unaffected ileum of CD [ileal-involved CD (iCD) and non-invloved ileal CD (cCD)], but not in the ileum of ulcerative colitis or control.
GSE58095 ImmunoHuman SystemicSclerosis 102 1 We identified fibro-inflammatory and keratin gene expression signatures in systemic sclerosis skin.
GSE58121 ImmunoHuman Psoriasis 18 2 To investigate differences in the kinetics of allergic contact dermatitis reactions in psoriasis patients, molecular changes in clinically non-involved skin of psoriasis patients was investigated
GSE58240 ImmunoHuman 2015Q2 32 1 To identify gene expression changes and pathways induced by interferon-ß (IFN-ß) in B cells, we studied the in vitro response of EBV-transformed B cells (lymphoblast cell lines-LCLs). LCLs were derived from an MS patient repository. Whole genome expression analysis identified 115 genes that were more than two-fold differentially up-regulated following IFN-ß exposure, with over 50 novel IFN-ß response genes. Pathways analysis demonstrated that IFN-ß affected LCLs in a similar manner to other cell types by activating known IFN-ß canonical pathways. Additionally, IFN-ß increased the expression of innate immune response genes, while down-regulating many B cell receptor pathway genes and genes involved in adaptive immune responses. Several of the novel response genes were tested and validated as IFN-ß response genes in human primary B cells.
GSE58364 ImmunoHuman AD 12 1 Methanol (MeOH) is considered to be a poison in humans because of the alcohol dehydrogenase (ADH)-mediated conversion of MeOH into toxic formaldehyde (FA). Our recent genome-wide analysis of the mouse brain demonstrated that an increase in endogenous MeOH after ADH inhibition led to a significant increase in the plasma MeOH concentration and the modification of mRNA synthesis. These findings suggest endogenous MeOH involvement in homeostasis regulation by controlling mRNA levels. Here, we demonstrate directly that study volunteers displayed increasing concentrations of MeOH and FA in their blood plasma when consuming citrus pectin, ethanol and red wine. A microarray analysis of white blood cells (WBC) in volunteers after pectin intake showed various responses for 30 differentially regulated mRNAs. Most of the mRNAs were somehow involved in the pathogenesis of Alzheimer's disease (AD). There was also a decreased synthesis of hemoglobin mRNA, HBA and HBB, the presence of which in WBC RNA was not a result of red blood cells contamination because erythrocyte-specific marker genes did not show significant change. A qRT-PCR analysis of volunteer WBC after pectin and red wine intake confirmed the complicated dependence between plasma MeOH content and the mRNA accumulation of previously identified genes, namely GAPDH and SNX27, and MME, SORL1, DDIT4, HBA and HBB genes revealed in this study. We hypothesized that human plasma MeOH, which is replenished from endogenous and exogenous sources (diet), has an impact on the WBC mRNA levels of genes involved in AD pathogenesis and signaling.
GSE58434 ImmunoHuman 2015Q2 53 5 Rationale: Asthma is a chronic inflammatory airway disease. Children with severe asthma have lower levels of vitamin D than children with moderate asthma, and among children with severe asthma, airway smooth muscle (ASM) mass is inversely related to vitamin D levels. Beta2 agonists are a common asthma medication that act partly by targetting the ASM. We used RNA-Seq to characterize the human ASM transcriptome of fatal and asthma vs. contols at baseline and under two treatment conditions.\r\nMethods: The Illumina TruSeq assay was used to prepare 75bp paired-end libraries for ASM cells from white donors, 6 with fatal asthma and 12 control donors under three treatment conditions: 1) no treatment; 2) treatment with a ß2-agonist (i.e. Albuterol, 1µM for 18h); 3) treatment with vitamin D 100 nM for 18h). Llibraries were sequenced with an Illumina Hi-Seq 2000 instrument. The Tuxedo Suite Tools were used to align reads to the hg19 reference genome, assemble transcripts, and perform differential expression analysis using the protocol described in https://github.com/blancahimes/taffeta
GSE58667 ImmunoHuman 2015Q2 15 1 Association of juvenile spondyloarthritis (jSpA) with the HLA-B27 genotype is well established, but there is little knowledge of other genetic factors with a role in disease development. The aim of the present study was to identify and confirm gene signatures and novel biomarkers in various cohorts of untreated and treated patients diagnosed with jSpA and other forms of juvenile idiopathic arthritis (JIA).\r\nDNA microarray gene expression was performed in 11 patients with jSpA and in four healthy controls, along with bioinformatics analysis of retrieved data (DAVID, GSEA, IPA).
GSE58898 ImmunoHuman nomodel 75 0 Systems biology approach to examine effects of seasonal flu vaccination in adults of different ages on gene expression, cytokine stimulation and serum cytokines with parameters such as immune senescence to uncover new markers and mechanisms behind failure of immune function in many older people.
GSE58943 ImmunoHuman nomodel 72 0 Systems biology approach to examine effects of seasonal flu vaccination in adults of different ages on gene expression, cytokine stimulation and serum cytokines with parameters such as immune senescence to uncover new markers and mechanisms behind failure of immune function in many older people.
GSE59071 ImmunoHuman IBD 116 3 Microarrays were used to analyze the gene expression in endoscopic-derived intestinal mucosal biopsies from patients with inflammatory bowel disease (IBD) and controls
GSE59294 ImmunoHuman Dermatitis 40 3 Atopic dermatitis (AD) is the most common inflammatory skin disease, with high unmet need for new therapies that are safe for chronic use. Emerging data suggest that TH2-cytokines play important roles in a variety of allergic and atopic conditions, including asthma and AD. In early phase clinical trials, dupilumab (a fully human monoclonal antibody against IL-4Ra that potently blocks IL-4 and IL-13 signaling) rapidly and markedly improved clinical measures in adults with either asthma (with elevated eosinophil counts) or moderate-to-severe AD. The pathomechanisms that may be impacted by IL-4/13 blockade in these disease settings have not yet been characterized in detail.\r\nTranscriptome analyses in pre- and post-treatment skin biopsies from patients with moderate-to-severe AD treated with dupilumab or placebo in two completed clinical trials
GSE59635 ImmunoHuman 2015Q2 72 8 We profiled gene expression from a stratified cohort of subjects to define influenza vaccine response in Young and Old
GSE59654 ImmunoHuman 2015Q2 156 13 We profiled gene expression from a stratified cohort of subjects to define influenza vaccine response in Young and Old
GSE60399 ImmunoHuman nomodel 5 0 Investigation of whole genome gene expression level changes of the dynamic gene profiling of peripheral blood mononuclear cells (PBMCs) from patients with AECOPD) on day1, 3 and 10, compared to the normal people and stable COPD patients.
GSE60424 ImmunoHuman 2015Q2 134 35 This study compared whole transcriptome signatures of 6 immune cell subsets and whole blood from patients with an array of immune-associated diseases. Fresh blood samples were collected from healthy subjects and subjects diagnosed type 1 diabetes, amyotrophic lateral sclerosis, and sepsis, as well as multiple sclerosis patients before and 24 hours after the first treatment with IFN-beta. At the time of blood draw, an aliquot of whole blood was collected into a Tempus tube (Invitrogen), while the remainder of the primary fresh blood sample was processed to highly pure populations of neutrophils, monocytes, B cells, CD4 T cells, CD8 T cells, and natural killer cells. RNA was extracted from each of these cell subsets, as well as the whole blood samples, and processed into RNA sequencing (RNAseq) libraries (Illumina TruSeq). Sequencing libraries were analyzed on an Illumina HiScan, with a target read depth of ~20M reads. Reads were demultiplexed, mapped to human gene models (ENSEMBL), and tabulated using HTSeq. Read count data were normalized by the TMM procedure (edgeR package).
GSE60572 ImmunoHuman Influenza 24 0 The RIG-I like receptor pathway is stimulated during RNA virus infection by interaction between cytosolic RIG-I and viral RNA structures that contain short hairpin dsRNA and 5’ triphosphate (5’ppp) terminal structure. In the present study, an RNA agonist of RIG-I was synthesized in vitro and shown to stimulate RIG-I-dependent antiviral responses at concentrations in the picomolar range. In human lung epithelial A549 cells, 5’pppRNA specifically stimulated multiple parameters of the innate antiviral response, including IRF3, IRF7 and STAT1 activation, andinduction of inflammatory and interferon stimulated genes - hallmarks of a fully functional antiviral response. Evaluation of the magnitude and duration of gene expression by transcriptional profiling identified a robust, sustained and diversified antiviral and inflammatory response characterized by enhanced pathogen recognition and interferon (IFN)signaling. Bioinformatics analysis further identified a transcriptional signature uniquely induced by 5’pppRNA, and not by IFNa-2bthat included a constellation of IRF7 and NF-kB target genes capable of mobilizing multiple arms of the innate and adaptive immune response. Treatment of primary PBMCs or lung epithelial A549 cells with 5’pppRNA provided significant protection against a spectrum of RNA and DNA viruses. In C57Bl/6 mice, intravenous administration of 5’pppRNA protected animals from a lethal challenge with H1N1 Influenza, reduced virus titers in mouse lungs and protected animals from virus-induced pneumonia. Strikingly, the RIG-I-specific transcriptional response afforded partial protection from influenza challenge, even in the absence of type I interferon signaling. This systems approach providestranscriptional, biochemical, and in vivo analysis of the antiviral efficacy of 5’pppRNA and highlights the therapeutic potential associated with the use of RIG-I agonists as broad spectrum antiviral agents.
GSE60573 ImmunoHuman nomodel 11 0 The RIG-I like receptor pathway is stimulated during RNA virus infection by interaction between cytosolic RIG-I and viral RNA structures that contain short hairpin dsRNA and 5’ triphosphate (5’ppp) terminal structure. In the present study, an RNA agonist of RIG-I was synthesized in vitro and shown to stimulate RIG-I-dependent antiviral responses at concentrations in the picomolar range. In human lung epithelial A549 cells, 5’pppRNA specifically stimulated multiple parameters of the innate antiviral response, including IRF3, IRF7 and STAT1 activation, andinduction of inflammatory and interferon stimulated genes - hallmarks of a fully functional antiviral response. Evaluation of the magnitude and duration of gene expression by transcriptional profiling identified a robust, sustained and diversified antiviral and inflammatory response characterized by enhanced pathogen recognition and interferon (IFN)signaling. Bioinformatics analysis further identified a transcriptional signature uniquely induced by 5’pppRNA, and not by IFNa-2bthat included a constellation of IRF7 and NF-kB target genes capable of mobilizing multiple arms of the innate and adaptive immune response. Treatment of primary PBMCs or lung epithelial A549 cells with 5’pppRNA provided significant protection against a spectrum of RNA and DNA viruses. In C57Bl/6 mice, intravenous administration of 5’pppRNA protected animals from a lethal challenge with H1N1 Influenza, reduced virus titers in mouse lungs and protected animals from virus-induced pneumonia. Strikingly, the RIG-I-specific transcriptional response afforded partial protection from influenza challenge, even in the absence of type I interferon signaling. This systems approach providestranscriptional, biochemical, and in vivo analysis of the antiviral efficacy of 5’pppRNA and highlights the therapeutic potential associated with the use of RIG-I agonists as broad spectrum antiviral agents.
GSE60762 ImmunoHuman 2015Q2 8 1 Osteoarthritic cartilage has largely been investigated, however supporting structures as the acetabular labrum are less investigated. In this studies we aimed to identify differences in gene expression between healthy and osteoarthritic labrum cells\r\nwe used the microarray as a discovery tool to identify possible new targets in hip osteoarthritis pathology
GSE60971 ImmunoHuman Psoriasis 24 6 Establishment of a transcriptomic profile of human cells treated with genistein with particular emphasis on the assessment of the role of this isoflavone in regulation of expression of psoriasis-related genes stands for the present study. The hypothesis tested was that genistein modulates activity of psoriasis-related genes, by reducing the expression efficiency of genes revealing enhanced activity in psoriatic cells, and by stimulating the expression efficiency of genes revealing decreased activity in psoriatic cells. Results provide important information concerning the extent of action of genistein at the molecular level in terms of modulation of gene expression by this substance. Keratinocytes were cultured from cryo-preserved cells in Dulbecco’s modified Eagle’s medium containing 10% fetal bovine serum and 1% antibiotic/antimycotic solution at 37 oC in a humidified atmosphere of 5% CO2. 10E5 cells were seeded in 6-well plates and grown to a confluence of approximately 80 %. The medium was replaced by fresh medium non-supplemented, containing dimethyl sulfooxide (DMSO) added to a final concentration of 0.05%, or genistein at 30, 60 and 100 µM concentrations, with 0.05% DMSO. The experimental treatment was carried out for 24 h and 48 h period. Total RNA was extracted from cells using the High Pure RNA Isolation Kit in accordance with the prescribed protocol, quantified with Quant iT RiboGreen Assay Kit.
GSE61141 ImmunoHuman 2015Q2 24 4 We report the application of RNA sequencing technology for high-throughput profiling of gene expression responses to human rhinovirus infection at 24 hours in air-liquid interface human airway epithelial cell cultures derived from 6 asthmatic and 6 non-asthmatic donors. RNA-seq analysis identified sets of genes associated with asthma specific viral responses. These genes are related to inflammatory pathways, epithelial remodeling and cilium assembly and function, including those described previously (e.g. CCL5, CXCL10 and CX3CL1), and novel ones that were identified for the first time in this study (e.g. CCRL1, CDHR3). We concluded that air liquid interface cultured human airway epithelial cells challenged with live HRV are a useful in vitro model for the study of rhinovirus induced asthma exacerbation, given that our findings are consistent with clinical data sets. Furthermore, our data suggest that abnormal airway epithelial structure and inflammatory signaling are important contributors to viral induced asthma exacerbation.
GSE61320 ImmunoHuman ALS 4 1 Senataxin, encoded by the SETX gene, contributes to multiple aspects of gene expression, including transcription and RNA processing. Mutations in SETX cause the recessive disorder ataxia with oculomotor apraxia type 2 (AOA2) and a dominant juvenile form of amyotrophic lateral sclerosis (ALS4). To assess the functional role of senataxin in disease, we examined differential gene expression in AOA2 patient fibroblasts, identifying a core set of genes showing altered expression by microarray and RNA-sequencing. To determine whether AOA2 and ALS4 mutations differentially affect gene expression, we overexpressed disease-specific SETX mutations in senataxin-haploinsufficient fibroblasts and observed changes in distinct sets of genes. This implicates mutation-specific alterations of senataxin function in disease pathogenesis and provides a novel example of allelic neurogenetic disorders with differing gene expression profiles. Weighted gene co-expression network analysis (WGCNA) demonstrated these senataxin-associated genes to be involved in both mutation-specific and shared functional gene networks. To assess this in vivo, we performed gene expression analysis on peripheral blood from members of 12 different AOA2 families and identified an AOA2-specific transcriptional signature. WGCNA identified two gene modules highly enriched for this transcriptional signature in the peripheral blood of all AOA2 patients studied. These modules were disease-specific and preserved in patient fibroblasts and in the cerebellum of Setx knockout mice demonstrating conservation across species and cell types, including neurons. These results identify novel genes and cellular pathways related to senataxin function in normal and disease states, and implicate alterations in gene expression as underlying the phenotypic differences between AOA2 and ALS4.
GSE61321 ImmunoHuman ALS 16 6 Senataxin, encoded by the SETX gene, contributes to multiple aspects of gene expression, including transcription and RNA processing. Mutations in SETX cause the recessive disorder ataxia with oculomotor apraxia type 2 (AOA2) and a dominant juvenile form of amyotrophic lateral sclerosis (ALS4). To assess the functional role of senataxin in disease, we examined differential gene expression in AOA2 patient fibroblasts, identifying a core set of genes showing altered expression by microarray and RNA-sequencing. To determine whether AOA2 and ALS4 mutations differentially affect gene expression, we overexpressed disease-specific SETX mutations in senataxin-haploinsufficient fibroblasts and observed changes in distinct sets of genes. This implicates mutation-specific alterations of senataxin function in disease pathogenesis and provides a novel example of allelic neurogenetic disorders with differing gene expression profiles. Weighted gene co-expression network analysis (WGCNA) demonstrated these senataxin-associated genes to be involved in both mutation-specific and shared functional gene networks. To assess this in vivo, we performed gene expression analysis on peripheral blood from members of 12 different AOA2 families and identified an AOA2-specific transcriptional signature. WGCNA identified two gene modules highly enriched for this transcriptional signature in the peripheral blood of all AOA2 patients studied. These modules were disease-specific and preserved in patient fibroblasts and in the cerebellum of Setx knockout mice demonstrating conservation across species and cell types, including neurons. These results identify novel genes and cellular pathways related to senataxin function in normal and disease states, and implicate alterations in gene expression as underlying the phenotypic differences between AOA2 and ALS4.
GSE61322 ImmunoHuman ALS 33 1 Senataxin, encoded by the SETX gene, contributes to multiple aspects of gene expression, including transcription and RNA processing. Mutations in SETX cause the recessive disorder ataxia with oculomotor apraxia type 2 (AOA2) and a dominant juvenile form of amyotrophic lateral sclerosis (ALS4). To assess the functional role of senataxin in disease, we examined differential gene expression in AOA2 patient fibroblasts, identifying a core set of genes showing altered expression by microarray and RNA-sequencing. To determine whether AOA2 and ALS4 mutations differentially affect gene expression, we overexpressed disease-specific SETX mutations in senataxin-haploinsufficient fibroblasts and observed changes in distinct sets of genes. This implicates mutation-specific alterations of senataxin function in disease pathogenesis and provides a novel example of allelic neurogenetic disorders with differing gene expression profiles. Weighted gene co-expression network analysis (WGCNA) demonstrated these senataxin-associated genes to be involved in both mutation-specific and shared functional gene networks. To assess this in vivo, we performed gene expression analysis on peripheral blood from members of 12 different AOA2 families and identified an AOA2-specific transcriptional signature. WGCNA identified two gene modules highly enriched for this transcriptional signature in the peripheral blood of all AOA2 patients studied. These modules were disease-specific and preserved in patient fibroblasts and in the cerebellum of Setx knockout mice demonstrating conservation across species and cell types, including neurons. These results identify novel genes and cellular pathways related to senataxin function in normal and disease states, and implicate alterations in gene expression as underlying the phenotypic differences between AOA2 and ALS4.
GSE61385 ImmunoHuman Arthritis 24 1 The anterior cruciate ligament (ACL) is an essential stabilizer of the tibiofemoral articulation. ACL tears often lead to functional instability and are associated with an increased risk for osteoarthritis. The healing potential of the injured ACL is poorly understood and is considered to be limited. Transcriptome-wide expression profiles of 24 human ACL remnants recovered at the time of surgical reconstruction were analyzed utilizing the Agilent human 8x60K microarray platform. Gene ontology was performed on differentially expressed transcripts based on time-from-injury (acute, <3 months; intermediate, 3-12 months; chronic, >12 months). A subset of transcripts was validated via microfluidic digital polymerase-chain-reaction. Expression of periostin, a highly differentially expressed transcript, was tested by immunohistochemistry. Numerous transcripts covering important functional classifications were differentially expressed by time-from-injury. In acute tears, processes representing angiogenesis were repressed while those representing stem-cell differentiation were elevated. In intermediate tears, processes representing stem-cell proliferation concomitant with cellular component organization/cellular localization were elevated. In chronic tears, processes denoting myosin filament organization were elevated while those representing cellular component organization/cell localization and extracellular matrix organization were repressed. Expression levels of periostin were down-regulated in chronic tears compared to acute (42-fold) and intermediate (29-fold) tears. Immunohistochemistry confirmed a decline in periostin expression in tissues from chronic tears. These findings suggest an initial attempt of the injured ACL to repair, which declines with time-from-injury. These findings have implications for efforts to repair the ACL and may be relevant for reconstruction of the ACL. The functional role of periostin in ACL injuries, and the potential implication for surgical treatment, warrants further investigation.
GSE61396 ImmunoHuman nomodel 18 0 Members of rhinovirus C (RV-C) species are more likely to cause wheezing illnesses and asthma exacerbations compared to other rhinoviruses. The cellular receptor for these viruses was heretofore unknown. We measured gene expression (Human Gene 1.0 ST Array, Affymetrix) in two series of experiments involving cells that were either susceptible or not susceptible to RV-C infection. In one experimental series, susceptible cells included whole sinus mucosal tissue specimens (n = 5), epithelial cell suspension from sinus tissue, and nasal epithelium obtained via brushing, while non-susceptible cells included monolayers of primary undifferentiated epithelial cells and transformed cell lines (n = 5). In a second experimental series, we compared three pairs of undifferentiated and fully differentiated (ALI) sinus epithelial cell cultures. We identified a total of 12 genes upregulated in RV-C susceptible cells (represented by 14 probe sets) encoding proteins localized to plasma membrane, and/or with predicted or functionally demonstrated receptor activity, including members of the Human MHC class II, stomatin, guanine nucleotide-binding, type I cytokine and atypical chemokine receptor and cadherin protein families.
GSE61635 ImmunoHuman 2015Q2 129 1 The goal of this study was to characterize gene expression profiles in RNP autoantibody+ SLE versus healthy blood donors with a focus on select cytokines that may be important in B cell activation and differentiation, including BAFF, IL-21, and IL-33. We utilized Affymetrix microarrays to characterize the global program of gene expression in the SLE patients, and to identify differentially expressed genes in patients compared to healthy controls. We examined a cohort of 79 consecutive patients classified as anti-ribonuclear protein (anti-RNP)+ systemic lupus erythematosus (SLE). All patients provided RNA samples obtained after providing informed consent. There were 73 female and 6 male subjects. Disease duration ranged from 0 to 453 months with a median of 37.5 months. SLE Disease Activity Index (SLEDAI) ranged from 0 to 31 with a median of 6.
GSE61754 ImmunoHuman 2015Q2 88 24 Despite increases in vaccination coverage, reductions in influenza-related mortality have not been observed. Better vaccines are therefore required and influenza challenge studies can be used to test the efficacy of new vaccines. However, this requires the accurate post-challenge classification of subjects by outcome, which is limited in current methods that use artificial thresholds to assign “symptomatic” and “asymptomatic” phenotypes. We present data from an influenza challenge study in which 22 healthy adults (11 vaccinated) were inoculated with H3N2 influenza (A/Wisconsin/67/2005). We generated genome-wide gene expression data from peripheral blood taken immediately before the challenge and at 12, 24, and 48 hours post-challenge. Variation in symptomatic scoring was found among those with laboratory confirmed influenza. By combining the dynamic transcriptomic data with the clinical parameters this variability can be reduced. We identified four subjects with severe laboratory confirmed flu that show differential gene expression in 1,103 probes 48 hours post-challenge compared to the remaining subjects. We have further reduced this profile to 6 genes that can be used to define these subjects. We have used this gene set to predict symptomatic infection from an independent study. This analysis gives further insight into host-pathogen interactions during influenza infection. However, the major potential value is in the clinical trial setting by providing a more quantitative method to better classify symptomatic individuals post influenza challenge.
GSE62207 ImmunoHuman IBD 310 4 We report the global pattern of ileal gene expression in a cohort of 310 treatment-naïve pediatric Crohn Disease patients and controls. We focus on genes with consistent altered expression in the ileum of younger (Paris age A1a) vs older (Paris age A1b) patients.
GSE62253 ImmunoHuman Inflammation 12 3 Silver nanoparticles are used in consumer products like food contact materials, drinking water technologies and supplements, due to their antimicrobial properties. This leads to an oral uptake and exposure of intestinal cells. In contrast to other studies we found no apoptosis induction by surfactant coated silver nanoparticles in the intestinal cell model Caco-2 in a previous study, although the particles induced oxidative stress, morphological changes and cell death. Therefore, this study aimed to analyze the molecular mechanism of silver nanoparticles in Caco-2 cells. We used global gene expression profiling in differentiated Caco-2 cells, supported by verification of the microarray data by quantitative real time RT-PCR and microscopic analysis, impedance measurements and assays for apoptosis and oxidative stress. Our results revealed that the majority of surfactant coated silver nanoparticles are not taken up into differentiated Caco-2 cells. and probably affect the cells by outside-in signaling. They induce oxidative stress and have an influence on canonical pathways related to FAK, ILK, ERK, MAPK, integrins and adherence and tight junctions, thereby inducing transcription factors like AP1, NF?B and NRF2, which mediate cellular reactions in response to oxidative stress and metal ions and induce changes in the cytoskeleton and cell-cell and cell-matrix contacts. The present data confirm the absence of apoptotic cell death. Non-apoptotic, necrotic cell death, especially in the intestine, can cause inflammation and influence the mucosal immune response.
GSE62331 ImmunoHuman BasicScience 31 2 Immune impairment and high circulating level of pro-inflammatory cytokines are landmarks of human aging. However, the molecular basis of immune dysregulation and the source of inflammatory markers remain unclear. Here we demonstrate that in the absence of overt cell stimulation, gene expression mediated by the transcription factor NF-?B is higher in purified and rested human CD4+ T lymphocytes from older compared to younger individuals. This increase of NF-?B -associated transcription includes transcripts for pro-inflammatory cytokines such as IL-1 and chemokines such as CCL2 and CXCL10. We demonstrate that NF-?B up-regulation is cell-intrinsic and mediated in part by phosphatidylinositol 3-kinase (PI3K) activity induced in response to metabolic activity, which can be moderated by rapamycin treatment. Our observations provide direct evidence that dysregulated basal NF-?B activity may contribute to the mild pro-inflammatory state of aging.
GSE62332 ImmunoHuman BasicScience 23 2 Immune impairment and high circulating level of pro-inflammatory cytokines are landmarks of human aging. However, the molecular basis of immune dysregulation and the source of inflammatory markers remain unclear. Here we demonstrate that in the absence of overt cell stimulation, gene expression mediated by the transcription factor NF-?B is higher in purified and rested human CD4+ T lymphocytes from older compared to younger individuals. This increase of NF-?B -associated transcription includes transcripts for pro-inflammatory cytokines such as IL-1 and chemokines such as CCL2 and CXCL10. We demonstrate that NF-?B up-regulation is cell-intrinsic and mediated in part by phosphatidylinositol 3-kinase (PI3K) activity induced in response to metabolic activity, which can be moderated by rapamycin treatment. Our observations provide direct evidence that dysregulated basal NF-?B activity may contribute to the mild pro-inflammatory state of aging.
GSE62373 ImmunoHuman BasicScience 45 2 Immune impairment and high circulating level of pro-inflammatory cytokines are landmarks of human aging. However, the molecular basis of immune dysregulation and the source of inflammatory markers remain unclear. Here we demonstrate that in the absence of overt cell stimulation, gene expression mediated by the transcription factor NF-?B is higher in purified and rested human CD4+ T lymphocytes from older compared to younger individuals. This increase of NF-?B -associated transcription includes transcripts for pro-inflammatory cytokines such as IL-1 and chemokines such as CCL2 and CXCL10. We demonstrate that NF-?B up-regulation is cell-intrinsic and mediated in part by phosphatidylinositol 3-kinase (PI3K) activity induced in response to metabolic activity, which can be moderated by rapamycin treatment. Our observations provide direct evidence that dysregulated basal NF-?B activity may contribute to the mild pro-inflammatory state of aging.
GSE62374 ImmunoHuman BasicScience 32 6 Immune impairment and high circulating level of pro-inflammatory cytokines are landmarks of human aging. However, the molecular basis of immune dysregulation and the source of inflammatory markers remain unclear. Here we demonstrate that in the absence of overt cell stimulation, gene expression mediated by the transcription factor NF-?B is higher in purified and rested human CD4+ T lymphocytes from older compared to younger individuals. This increase of NF-?B -associated transcription includes transcripts for pro-inflammatory cytokines such as IL-1 and chemokines such as CCL2 and CXCL10. We demonstrate that NF-?B up-regulation is cell-intrinsic and mediated in part by phosphatidylinositol 3-kinase (PI3K) activity induced in response to metabolic activity, which can be moderated by rapamycin treatment. Our observations provide direct evidence that dysregulated basal NF-?B activity may contribute to the mild pro-inflammatory state of aging.
GSE62375 ImmunoHuman BasicScience 10 6 Immune impairment and high circulating level of pro-inflammatory cytokines are landmarks of human aging. However, the molecular basis of immune dysregulation and the source of inflammatory markers remain unclear. Here we demonstrate that in the absence of overt cell stimulation, gene expression mediated by the transcription factor NF-?B is higher in purified and rested human CD4+ T lymphocytes from older compared to younger individuals. This increase of NF-?B -associated transcription includes transcripts for pro-inflammatory cytokines such as IL-1 and chemokines such as CCL2 and CXCL10. We demonstrate that NF-?B up-regulation is cell-intrinsic and mediated in part by phosphatidylinositol 3-kinase (PI3K) activity induced in response to metabolic activity, which can be moderated by rapamycin treatment. Our observations provide direct evidence that dysregulated basal NF-?B activity may contribute to the mild pro-inflammatory state of aging.
GSE62520 ImmunoHuman IBD 16 3 BACKGROUND & AIMS- More frequent interaction of bacteria with the colonic epithelium is associated with ulcerative colitis (UC). The identities of all proteins which promote bacterial clearance in colonic epithelial cells are unknown. Previously, we discovered that dCAP-D3 (Chromosome Associated Protein-D3), regulates responses to bacterial infection. We examined whether CAP-D3 promotes bacterial clearance in human colonic epithelium.\r\nMETHODS- Clearance of Salmonella or adherent-invasive Escherichia coli LF82 was assessed by gentamycin protection assays in HT-29 and Caco-2 cells expressing CAP-D3 shRNA. CAP-D3 levels in colonic epithelial cells from healthy and UC patient tissues were analyzed by immunoblot. RNA-sequencing identified bacterially-induced CAP-D3 target genes. The role of CAP-D3 target genes in bacterial clearance was analyzed by gentamycin protection assays, immunofluorescent staining, and by using pharmacologic inhibitors.\r\nRESULTS- CAP-D3 expression was reduced in colonic epithelial cells from UC patients with active disease. Reduction of CAP-D3 expression inhibited autophagy and decreased intracellular bacterial clearance. The components of the heterodimeric SLC7A5/SLC3A2 amino acid transporter were identified as CAP-D3 target genes; their levels increased in infected, CAP-D3 deficient cell lines and in cells from UC patients. In HT-29 cells, this resulted in earlier SLC7A5 recruitment to Salmonella-containing vacuoles, increased mTOR activity, and enhanced bacterial survival. Inhibition of SLC7A5/SLC3A2 or mTOR activity rescued the bacterial clearance defect in CAP-D3 deficient cells.\r\nCONCLUSIONS- CAP-D3 attenuates amino acid transporter transcription to promote bacterial autophagy in colon epithelial cells. CAP-D3 protein levels are decreased in patients with active UC, suggesting that CAP-D3 is a potential therapeutic target to restore mucosal homeostasis in UC patients.
GSE62584 ImmunoHuman 2015Q2 60 4 Optic neuritis (ON) is a common manifestation of multiple sclerosis (MS); it appears as the presenting symptom in about 25% of MS patients and occurs in 30–70% of patients with MS during the course of their illness\r\nPurpose. To evaluate the molecular pathways that operate in the early phase of acute ON by studying gene expression profiles of peripheral blood mononuclear cells (PBMCs) subpopulations including CD19+ B cells, CD14+ macrophages, CD4+ and CD8+ T cells.
GSE6269 ImmunoHuman 2015Q2 143 13 Each infectious agent represents a unique combination of pathogen-associated molecular patterns that interact with specific pattern-recognition receptors expressed on immune cells. Therefore, we surmised that the blood immune cells of individuals with different infections might bear discriminative transcriptional signatures. Gene expression profiles were obtained for 131 peripheral blood samples from pediatric patients with acute infections caused by influenza A virus, Gram-negative (Escherichia coli) or Gram-positive (Staphylococcus aureus and Streptococcus pneumoniae) bacteria. Thirty-five genes were identified that best discriminate patients with influenza A virus infection from patients with either E coli or S pneumoniae infection. These genes classified with 95% accuracy (35 of 37 samples) an independent set of patients with either influenza A, E coli, or S pneumoniae infection. A different signature discriminated patients with E coli versus S aureus infections with 85% accuracy (34 of 40). Furthermore, distinctive gene expression patterns were observed in patients presenting with respiratory infections of different etiologies. Thus, microarray analyses of patient peripheral blood leukocytes might assist in the differential diagnosis of infectious diseases.
GSE6276 ImmunoHuman AD 6 2 Regulation of presenilin genes. Presenilins are intramembrane aspartic proteases. These proteases are critical proteins in pathogenesis of Alzheimer's disease. The function of recently identified presenilin-homologous proteases (IMPAS or SPP)s is unknown. Our preliminary data in C.elegans model suggested the role of these proteins in early-development and , perhaps, in pathway related- to cholesterol -regulated signalling (Grigorenko et al, 2004, PNAS).\r\nThe overall goal is to determine pattern of gene expression alterations in cells with knock-out or knock-down presenilin related proteins (IMPAS). The cultured cells, C.elegans and mouse models are planned to be used in this study. Initially, we will determine gene expression patterns in human cells embryonic kidney cells (HEK 293 cell line) overexpressing different isoforms of hIMP1 protein.\r\nWe hypothesize that novel family of presenilin-related proteases is important for cholesterol-regulated intracellular signalling and early development (including CNS/neuronal development and function).\r\nWe will examine in HEK 293 cells effect of over expression of 1) hIMP1 wt protein, 2) over expression of dominant negative isoform of hIMP1 protein and compare their gene expression patterns to 3) HEK 293 cells treated with mock vector. HEK 293 cells were seeded on 10 cm plates and transfected next day using Lipofectamine Plus reagent. 24 hours after cells were washed twice with ice cold PBS buffer and lysed with TRizol reagent directly on plates. Total RNA was extracted, purified according the manufacturer protocol and stored at -800C. We will provide 2 RNA samples for each hIMP1 isoform used in two different transfection experiment to reduce any spurious expression differences resulting from culture condition or transfection efficiency variations.
GSE62974 ImmunoHuman COPD 6 1 Purpose: By integrating DNA methylation and gene expression of COPD lung tissues, we identified EPAS1 as a key regulator whose downstream genes significantly overlapped with multiple genes sets associated with COPD disease severity. EPAS1 is distinct in comparison with other key regulators in terms of methylation profiles and downstream target genes. Genes predicted to be regulated by EPAS1 were enriched for biological processes including signaling, cell communications, and system developement. As EPAS1 downstream genes were significantly enriched for hypoxia responsive genes in endothelial cells, we tested EPAS1 function in human and mouse endothelial cells HUVEC and C166. EPAS1 knockdown by siRNA in endothelial cells impacted genes that significantly overlapped with EPAS1 downstream genes in lung tissue including hypoxia responsive genes.\r\nMethods: The cell lines of HUVEC (Lonza, MD, USA) and C166 (American Type Culture Collection, VA, USA) were cultured in the appropriate media at 37°C with 5% CO2. The cells were transfected with EPAS1 siRNA and non-targeting negative control siRNA (Life Technologies, CA, USA) using Lipofectamine RNAiMAX as recommended transfection protocols by the manufacturer. After the treatments with 5nM Silencer® Select siRNA (s4700 for EPAS1, s65525 for Epas1; Life Technologies, USA) for 48 hours, the total RNA was purified with RNeasy Mini Kit (QIAGEN, Germany). The efficiencies of knocked down the EPAS1 expression were assessed by qPCR with 1.4% for HUVEC, 3.2% for C166. Approximately 250 ng of total RNA per sample were used for library construction by the TruSeq RNA Sample Prep Kit (Illumina) and sequenced using the Illumina HiSeq 2500 instrument with 100nt single read setting according to the manufacturer's instructions. Sequence reads were aligned to human genome assembly hg19 and mouse genome assembly mm10, respectively, using Tophat [96]. Total 23,228 human and 22,609 mouse genes were quantified using Cufflinks [96]. siRNA signatures were derived by comparing expression profiles of EPAS1 or Epas1 siRNAs with non-targeting siRNAs at paired t-test p-value cutoff 0.05 with resulting signature sizes of 2,796 and 3,730, and corresponding q-values [97] 0.11 and 0.07 for HUVEC and C166, respectively.\r\nResults: When comparing endothelial cells treated with EPAS1 siRNAs and scrambled siRNAs, we identified an EPAS1 siRNA signature consisting of 2796 and 3730 genes in human and mouse endothelial cell lines, respectively, whose expression levels significantly changed (t-test p-value<0.05), including EPAS1 itself (p-value = 0.002 and 0.02) and the EPAS1 downstream target gene VEGFA (p-value = 0.03 and 0.01). The EPAS1 siRNA signatures derived from human and mouse cell lines were highly consistent, with 695 genes in common to both signatures (p-value = 7.2x10-65). Both signatures not only significantly overlapped with EPAS1 downstream genes (p-value = 7.3x10-7 and 1.5x10-12), but also with hypoxia response genes in endothelial cells (Fisher’s Exact Test p-value = 5.8x10-8 and 1.2x10-12 in the human and mouse signatures, respectively). Moreover, the EPAS1 siRNA signatures consistently overlapped genes associated with the COPD severity phenotypes. These results together validate that EPAS1 causally regulates the downstream target genes we predicted, and that these genes in turn affect COPD development and progression.
GSE63060 ImmunoHuman AD 329 2 Alzheimer case-control samples originate from the EU funded AddNeuroMed Cohort, which is a large cross-European AD biomarker study relying on human blood as the source of RNA.
GSE63061 ImmunoHuman AD 388 3 Alzheimer case-control samples originate from the EU funded AddNeuroMed Cohort, which is a large cross-European AD biomarker study relying on human blood as the source of RNA.
GSE63079 ImmunoHuman Psoriasis 6 1 To determne JunB target gene in human keratincoytes\r\nMice with epidermal deletion of JunB transcription factor displayed a psoriasis-like inflammation. The relevance of these findings to humans and the mechanisms mediating JunB function are not fully understood. Here, we demonstrate that impaired JunB function via gene silencing or overexpression of a dominant negative mutant increased human keratinocyte cell proliferation but decreased cell barrier function. RNA-seq revealed over 500 genes affected by JunB loss-of-function which included an upregulation of an array of proinflammatory molecules relevant to psoriasis. Among these were TNFa, CCL2, CXCL10, IL6R and SQSTM1, an adaptor protein involved in NF-kB activation. ChIP-Seq and gene reporter analyses showed that JunB directly suppressed SQSTM1 through binding to a consensus AP-1 cis-element located around 2 Kb upstream of SQSTM1-trasncription start site. Similar to JunB loss-of-function, SQSTM1-overexpression induced TNFa, CCL2 and CXCL10. Conversely, NF-kB-inhibition genetically with a mutant IkBa or pharmacologically with PDTC prevented cytokine, but not IL6R, induction by JunB-deficiency. Taken together, our findings indicate that JunB controls epidermal growth, barrier formation and proinflammatory responses through direct and indirect mechanisms, pinpointing SQSTM1 as a key mediator of JunB-suppression of NF-kB-dependent inflammation.
GSE63142 ImmunoHuman 2015Q2 155 2 Bronchial Epithelial Cells were isolated processed as described (Chu et al., 2002 and Zhao et al., 2011). The objective of the study was to identify differentially expressed genes between normal control (NC), mild-moderate asmathic (notSA) and severe asthmatic (SA) patients. For demographics data, contact Dr.Sally Wenzel (wenzelse@upmc.edu)
GSE63383 ImmunoHuman 2015Q2 24 10 Persistent severe asthma is associated with hyper-contractile airways and structural changes in the airway wall, including an increased airway smooth muscle (ASM) mass. This study used gene expression profiles from asthmatic and healthy airway smooth muscle cells grown in culture to identify novel receptors and pathways that potentially contributed to asthma pathogenesis.\r\nWe used microarrays to compare the gene expression between asthmatic and healthy airway smooth muscle cells to understand the underlying pathway contributing the differences in cellular phenotypes
GSE63662 ImmunoHuman ChronicInflammation 6 1 Human and murine studies showed that granulocyte macrophage colony-stimulating factor (GM-CSF) exerts beneficial effects in intestinal inflammation. To explore whether GM-CSF mediates its effects via monocytes, we analyzed effects of GM-CSF on monocytes in vitro and assessed the immunomodulatory potential of GM-CSF-activated monocytes (GMaM). We used microarray technology and functional assays to characterize GMaM in vitro and used a mouse model of colitis to study GMaM functions in vivo.
GSE63755 ImmunoHuman SLE 7 2 Constitutive low level DNA damage in RNASEH2 deficiency is linked to innate immune activation. Hierarchical clustering of over 16000 transcripts revealed remarkably similar profiles in patients with lupus erythematosus and patients with AGS with up-regulation of genes involved in DNA damage signaling and type I-IFN signaling.
GSE63816 ImmunoHuman 2015Q2 22 4 Somatic mutations in the spliceosome gene ZRSR2— located on the X chromosome — are associated with myelodysplastic syndrome (MDS). ZRSR2 is involved in the recognition of 3? splice site during the early stages of spliceosome assembly; however, its precise role in RNA splicing has remained unclear. Here, we characterize ZRSR2 as an essential component of the minor spliceosome (U12-dependent) assembly. shRNA mediated knockdown of ZRSR2 leads to impaired splicing of the U12-type introns, and RNA-Sequencing of MDS bone marrow reveals that loss of ZRSR2 activity causes increased mis-splicing. These splicing defects involve retention of the U12-type introns while splicing of the U2-type introns remain mostly unaffected. ZRSR2 deficient cells also exhibit reduced proliferation potential and distinct alterations in myeloid and erythroid differentiation in vitro. These data identify a specific role for ZRSR2 in RNA splicing and highlight dysregulated splicing of U12-type introns as a characteristic feature of ZRSR2 mutations in MDS.
GSE63903 ImmunoHuman LungDisease 14 1 Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular damage, and fibrosis of the skin and internal organs. Because activated and oligoclonally expanded CD8+ T cells can be detected in peripheral blood and lung of SSc patients, effector memory CD8+ T cells may play a critical role for organ involvement in SSc; however, the pathogenic functions of effector memory CD8+ T cells remain incompletely understood. Here we performed DNA microarray analysis of the sort-purified effector memory CD8+ T cells from SSc patients and healthy controls, and showed that the expression of genes related to immune response and cell adhesion, including CD226 (also known as DNAX accessory molecule-1, DNAM-1), was significantly altered. Moreover, detailed analysis of CD226 revealed that CD226highCD8+ T cells were increased in SSc patients (mean, 50.7%) compared with healthy controls (32.9%) and were appreciably associated with the severity of skin sclerosis and interstitial lung disease. Further, CD226highCD8+ T cells from SSc patients produced abundant IL-13 and were positively correlated with the cytotoxic capacity of CD8+ T cells against HUVECs. Finally, the neutralization of CD226 impaired IL-13 production and cytolysis against HUVECs. These findings indicate that upregulated CD226 expression on CD8+ T cells reflects disease severity and are involved in SSc pathogenesis via the production of profibrotic IL-13 and endothelial cell injury, and that CD226 may be a useful target in the treatment of SSc.
GSE63980 ImmunoHuman 2015Q2 216 3 This SuperSeries is composed of the SubSeries listed below.
GSE63995 ImmunoHuman 2015Q2 8 1 TNF-like ligand 1A (TL1A) is a member of TNF receptor superfamily and involved in the pathogenesis of autoimmune diseases by inducing apoptosis via intracellular death domain or promoting inflammation through the activation of NF?B by binding to its specific receptor death receptor 3 (DR3). Meanwhile, decoy receptor 3 (DcR3) competitively binds soluble TL1A in addition to Fas-ligand (FasL) and LIGHT and inhibits the signaling of TL1A via DR3. DcR3 overexpressed in rheumatoid synovial fibroblasts (RA-FLS) stimulated with inflammatory cytokines such as TNFa or IL-1ß inhibits Fas-induced apoptosis. In contrast, DcR3 inhibited cell proliferation induced by inflammatory cytokines via membrane-bound TL1A expressed on RA-FLS. Therefore, TL1A-DcR3/DR3 signaling may be involved in the pathogenesis of RA by modulating apoptosis and proliferation of RA-FLS.\r\nWe hypothesized that TL1A regulates the gene expression in RA-FLS. We used to search for genes in which expression in RA-FLS is regulated by the ligation of TL1A.
GSE64028 ImmunoHuman BasicScience 20 3 Human PB B cell subsets are functionally distinct and may derive from different developmental pathways, reflected by their differential gene expression profiles.\r\nWe used microarrays to detail the global programme of gene expression underlying germinal center transition and functional propensities of individual subsets according to surface receptor and cell adhesion molecule expression.
GSE64394 ImmunoHuman Arthritis 7 1 Examination of the genome-wide distribution of 5hmC in osteoarthritic chondrocytes compared to normal chondrocytes in order to elucidate the effect on OA-specific gene expression.\r\n5hmC-sequencing was performed and data was compared with microarray gene expression data to identify genes with differential expression between normal and OA chondrocytes that are potentially under epigenetic regulation.
GSE64514 ImmunoHuman nomodel 71 0 Systems biology approach to examine effects of seasonal flu vaccination in adults of different ages on gene expression, cytokine stimulation and serum cytokines with parameters such as immune senescence to uncover new markers and mechanisms behind failure of immune function in many older people.
GSE64583 ImmunoHuman ALS 9 1 We have generated human induced Pluripotent Stem cells (hiPSc) from amyotrophic lateral sclerosis (ALS, motor neuron disease) patients, using Sendai virus-mediated delivery of reprogramming factors. hiPSc lines have been screened using SNP array to assess chromosomal stability (alongside the fibroblast lines from which they derived), and validation of the pluripotency of the hiPSc lines is provided by Pluritest assessment of transcriptome datasets, prior to differentiation to motor neuron cultures and downstream functional assays.\r\nMutihac R., Scaber J., Lalic T., Ababneh N., Vowles, J., Fletcher-Jones A., Douglas A.G.L., Browne C., Nakanishi M., Turner M., Wade-Martins R., Cowley S.A. and Talbot K. Altered ER calcium homeostasis and stress granule formation in iPSC-derived motor neurons from ALS/FTD patients with C9orf72 expansions. Submitted
GSE64655 ImmunoHuman 2015Q2 56 21 Systems biology is an approach to comprehensively study complex interactions within a biological system. Most published systems vaccinology studies have utilized whole blood or peripheral blood mononuclear cells (PBMC) to monitor the immune response after vaccination. Because human blood is comprised of multiple hematopoietic cell types, the potential for masking responses of under-represented cell populations is increased when analyzing whole blood or PBMC. To investigate the contribution of individual cell types to the immune response after vaccination, we established a rapid and efficient method to purify human T and B cells, natural killer (NK) cells, myeloid dendritic cells (mDC), monocytes, and neutrophils from fresh venous blood. Purified cells were fractionated and processed in a single day. RNA-Seq and quantitative shotgun proteomics were performed to determine expression profiles for each cell type prior to and after inactivated seasonal influenza vaccination. Our results show that transcriptomic and proteomic profiles generated from purified immune cells differ significantly from PBMC. Differential expression analysis for each immune cell type also shows unique transcriptomic and proteomic expression profiles as well as changing biological networks at early time points after vaccination. This cell type-specific information provides a more comprehensive approach to monitor vaccine responses.
GSE64712 ImmunoHuman Arthritis 7 1 During activation, T cells integrate multiple signals from APCs and cytokine milieu. The blockade of these signals can have clinical benefits as exemplified by CTLA4-Ig, which blocks interaction of B7 co-stimulatory molecules on APCs with CD28 on T cells. Variants of CTLA4-Ig, abatacept and belatacept are FDA approved as immunosuppressive agents in arthritis and transplantation whereas murine studies suggested that CTLA4-Ig can be beneficial in a number of other diseases. However, detailed analysis of human CD4 cell hyporesponsivness induced by CTLA4-Ig has not been performed. Herein, we established a model to study effect of CTLA4-Ig on the activation of human naïve T cells in a human mixed lymphocytes system. Comparison of human CD4 cells activated in the presence or absence of CTLA4-Ig, showed that co-stimulation blockade during TCR activation does not affect NFAT signaling but results in decreased activation of NF-kB and AP-1 transcription factors followed by profound decrease in proliferation and cytokine production. The resulting T cells become hyporesponsive to secondary activation and, although capable of receiving TCR signals, fail to proliferate or produce cytokines, demonstrating properties of anergic cells. However, unlike some models of T cell anergy, these cells did not possess increased levels of TCR signaling inhibitor CBLB. Rather, the CTLA4-Ig induced hyporesponsiveness was associated with an elevated level of p27kip1 cyclin-dependent kinase inhibitor.
GSE64801 ImmunoHuman IBD 14 1 Necrotizing enterocolitis (NEC) is the most frequent life-threatening gastrointestinal disease experienced by premature infant occuring in neonatal intensive care units. NEC is associated with severe intestinal inflammation, intestinal perforation leading to mortality. The challenge for neonatologists is to detect early clinical manifestations of NEC. Therefore, one of the strategies to prevent or treat NEC would be to develop an early diagnostic tool allowing identification of preterm infants either at risk of developing NEC or at the onset of the disease. Illumina’s deep sequencing technology (RNA-seq) was used to establish the gene expression profile between resected ileal healthy preterm (control, n=5) and NEC diagnosed preterm infant (NEC, n=9) and analyzed by IPA Core analysis system. IPA analysis indicated that the most significant functional pathways overrepresented in NEC neonates were associated with innate immune functions, such as altered T and B cell signaling, B cell development, and the role of pattern recognition receptors in recognition of bacteria and viruses. Among genes that were strongly modulated in NEC neonates, we observed a high degree of similarity with those linked to the development of IBD. By comparing gene expression patterns between NEC and Crohn’s disease, we identified several new potential protein targets for helping to predict and/or diagnose NEC in preterm infant. Gene expression profile revealed an uncontrolled innate immune response in the intestine of NEC neonates. Moreover, comparative analysis between NEC and Crohn’s disease evidenced high degree of similarity between these two inflammatory diseases and allowed us to identify several new potential NEC biomarkers.
GSE64922 ImmunoHuman Arthritis 8 1 Inflammation-mediated oncogenesis has been implicated in a variety of cancer types. Rheumatoid synovial tissues can be viewed as a tumor-like mass, consisting of hyperplastic fibroblast-like synoviocytes (FLSs). FLSs of rheumatoid arthritis (RA) patients have pro-migratory and invasive characteristics, which may be caused by chronic exposure to genotoxic stimuli, including hypoxia and growth factors. We tested whether a transformed phenotype of RA-FLSs is associated with placental growth factor (PlGF), a representative angiogenic growth factor induced by hypoxia. Here, we identified PlGF-1 and PlGF-2 as the major PlGF isoforms in RA-FLSs. Global gene expression profiling revealed that cell proliferation, apoptosis, angiogenesis, and cell migration were mainly represented by differentially expressed genes in RA-FLSs transfected with siRNA for PlGF. Indeed, PlGF-deficient RA-FLSs showed a decrease in cell proliferation, migration, and invasion, but an increase in apoptotic death in vitro. PlGF gene overexpression resulted in the opposite effects. Moreover, exogeneous PlGF-1 and PlGF-2 increased survival, migration, and invasiveness of RA-FLSs by binding their receptors, Flt-1 and NP-1, up-regulating the expression of anti-apoptotic molecules, pErk and Bcl2. Knock-down of PlGF transcripts reduced RA-FLS proliferation in a xeno-transplantation model. Collectively, in addition to their role for neovascularization, PlGF-1 and -2 promote proliferation, survival, migration, and invasion of RA-FLSs in an autocrine and paracrine manner. These results demonstrated how primary cells of mesenchymal origin acquired an aggressive and transformed phenotype. PlGF and its receptors thus offer new targets for anti-FLS therapy.
GSE65010 ImmunoHuman Arthritis 48 4 Objective: Conflicting evidence exists regarding the suppressive capacity of Tregs from the peripheral blood (PB) of patients with rheumatoid arthritis (RA). Our aim was to determine whether Tregs are intrinsically defective in RA using a wide range of read-out assays. Methods: CD3+CD4+CD25+CD127low Tregs from CD45RO+ and CD45RA+ compartments of PB from patients with RA and healthy controls (HC) were analysed for phenotype, cytokine expression profile (ex vivo and after in vitro stimulation), suppression of effector T-cell proliferation and cytokine production, suppression of monocyte-derived cytokine/chemokine production, and gene expression profiling. Results: No differences were observed between patients with RA and HC regarding Treg frequency, ex vivo phenotype (CD4, CD25, CD127, CD39, CD161) or pro-inflammatory cytokine profile (IL-17, IFN-gamma, TNF-alpha). FOXP3 expression was increased in Tregs from RA blood. The ability of Tregs to suppress T-cell proliferation or cytokine (IFN-gamma, TNF-alpha) production upon co-culture with autologous CD45RO+ effector T-cells and monocytes was not significantly different between patients with RA and HC. CD45RO+ Tregs from RA blood showed a slightly impaired ability to suppress production of some cytokines/chemokines by autologous LPS-activated monocytes (IL-1-beta, IL-1Ra, IL-7, CCL3, CCL4), but this was not true for all patients and other cytokines/chemokines (TNF-alpha, IL-6, IL-8, IL-12, IL-15, CCL5) were suppressed in the majority of patients similarly to HC. Finally, gene expression profiling of CD45RA+ or CD45RO+ Tregs from PB revealed no statistically significant differences between patients with RA and HC. Conclusions: Our findings suggest that Tregs isolated from PB of patients with RA are not intrinsically defective.
GSE65114 ImmunoHuman IBD 28 4 Expression data was used to evaluate changes to the transcriptional signatures across the healthy and inflamed colon. A comparison between healthy controls and active ulcerative colitis signatures was also made.
GSE65204 ImmunoHuman Asthma 69 1 We compared genomic DNA methylation patterns and gene expression in African American children with persistent atopic asthma versus healthy controls. We identified 119 differentially methylated regions (DMRs) and 118 differentially methylated probes (DMPs) after adjustment for age, gender, race/ethnicity, batch effects, inflation, and multiple comparisons (false discovery rate-adjusted q<0.05). Genes differentially methylated include those with established roles in asthma and atopy, components of the extracellular matrix, genes related to immunity, cell adhesion, epigenetic regulation, and airway obstruction. Hypo- and hypermethylated genes were associated with increased and decreased gene expression respectively (P<2.8x10-6 for DMRs and P<7.8x10-10 for DMPs). Quantitative analysis of methylation-expression relationships in 53 differentially expressed genes demonstrated that 32 (60%) have significant (q<0.05) methylation-expression relationships within 5kb of the gene. 10 loci selected based on the relevance to asthma, magnitude of methylation change, and asthma specific methylation-expression relationships were validated in an independent cohort of children with asthma.
GSE65270 ImmunoHuman nomodel 273 0 Pouchitis is a common complication for ulcerative colitis (UC) patients with ileal pouch-anal anastomosis (IPAA) surgery. Similarly to IBD, both innate host factors such as genetics, and environmental stimuli including the tissue-associated microbiome have been implicated in the pathogenesis. In this study, we make use of the IPAA model of inflammatory bowel disease (IBD) to carry out a study associating mucosal host gene expression with the microbiome and corresponding clinical outcomes.
GSE65336 ImmunoHuman SystemicSclerosis 78 2 Type I IFNs are implicated in the pathophysiology of systemic sclerosis (SSc). Recently, a Phase I open-label trial was conducted with an anti-IFNAR1 receptor antibody (anifrolumab) in adult SSc patients. In this study, we aim to assess the downstream effects of anifrolumab and elucidate the role of type I IFN in SSc. Serum proteins and extracellular matrix (ECM) markers were measured in relation to IFN pathway activation status and SSc disease activity. Our results demonstrated a robust overexpression of multiple serum proteins in SSc patients, particularly those with an elevated baseline type I IFN gene signature. Anifrolumab administration was associated with significant downregulation of T cell–associated proteins and upregulation of type III collagen degradation marker. Whole-blood and skin microarray results also indicated the inhibition of T cell receptor and ECM–related transcripts by anifrolumab. In summary, our study demonstrates suppressive effects of anifrolumab on T cell activation and collagen accumulation through which tissue fibrosis may be reduced in SSc patients. The relationship between these peripheral markers and the clinical response to anifrolumab may be examined in larger double-blind, placebo-controlled trials.
GSE65391 ImmunoHuman SLE 996 1 The goal of the study was to identify transcriptional correlates of SLE disease activity both at the cohort and at the individual levels. To do so, we longitudinally profiled the whole blood transcriptomes of 158 SLE patients by microarray for up to 4 years, yielding 924 SLE samples and 48 matched pediatric healthy samples. The transcriptional data are complemented by demographic, laboratory and clinical data.
GSE65790 ImmunoHuman IBD 6 2 A human gut-on-a-chip microdevice was used to coculture multiple commensal microbes in contact with living human intestinal epithelial cells for more than a week in vitro and to analyze how gut microbiome, inflammatory cells, and peristalsis-associated mechanical deformations independently contribute to intestinal bacterial overgrowth and inflammation. This in vitro model replicated results from past animal and human studies, including demonstration that probiotic and antibiotic therapies can suppress villus injury induced by pathogenic bacteria. By ceasing peristalsis-like motions while maintaining luminal flow, lack of epithelial deformation was shown to trigger bacterial overgrowth similar to that observed in patients with ileus and inflammatory bowel disease. Analysis of intestinal inflammation on-chip revealed that immune cells and lipopolysaccharide endotoxin together stimulate epithelial cells to produce four proinflammatory cytokines (IL-8, IL-6, IL-1ß, and TNF-a) that are necessary and sufficient to induce villus injury and compromise intestinal barrier function. Thus, this human gut-on-a-chip can be used to analyze contributions of microbiome to intestinal pathophysiology and dissect disease mechanisms in a controlled manner that is not possible using existing in vitro systems or animal models.
GSE6613 ImmunoHuman PD 105 6 Parkinson’s disease (PD) progresses relentlessly and affects five million people worldwide. Laboratory tests for PD are critically needed for developing treatments designed to slow or prevent progression of the disease. We performed a transcriptome-wide scan in 105 individuals to interrogate the molecular processes perturbed in cellular blood of patients with early-stage PD. The molecular marker here identified is strongly associated with risk of PD in 66 samples of the training set (third tertile cross-validated odds ratio of 5.7 {P for trend 0.005}). It is further validated in 39 independent test samples (third tertile odds ratio of 5.1 {P for trend 0.04}). The genes differentially expressed in patients with PD, or Alzheimer’s or progressive supranuclear palsy offer unique insights into disease-linked processes detectable in peripheral blood. Combining gene expression scans in blood and linked clinical data will facilitate the rapid characterization of candidate biomarkers as demonstrated here with respect to PD.
GSE66207 ImmunoHuman IBD 33 1 There is a need for reliable prognostic markers that can guide therapeutic intervention in Crohn’s disease (CD). We examined whether different behavioral phenotypes in CD can be classified based on colonic miRNA or mRNA expression and if miRNAs have prognostic utility for CD. We perform high-throughput sequencing of small RNA and mRNA isolated from colon tissue from CD patients and non-IBD (NIBD) controls. To identify miRNA and genes associated with specific behavioral phenotypes of CD, patients were stratified according to disease behavior (non-stricturing, non-penetrating; stricturing; penetrating) and compared miRNA profiles in each class with those of the NIBD group. Using a novel statistical simulation approach applied to colonic RNA-seq data for CD patients and NIBD controls, we identify at drivers of gene expression profiles associated with CD.
GSE66333 ImmunoHuman AD 8 1 High levels of oxidative stress and an associated neuronal DDR occur at the earliest stages of Alzheimer pathology (low Braak stage), and is associated with cognitive impairment.\r\nThe aim of the present study was to combine immuno-LCM and microarray analysis to characterize the neuronal transcriptome at low Braak stages (Braak 0-II), with respect to the neuronal DDR, in post-mortem human frontal cortex derived from the Medical Research Council Cognitive Function and Ageing Study (MRC-CFAS).
GSE66486 ImmunoHuman Influenza 18 2 IRF7 plays a critical role in the production and amplification of the antiviral type I and III interferon response. Autosomal recessive IRF7-deficiency resulted in life-threatening influenza disease in a 3-year-old child. We studied the impact of IRF7-deficiency in non-hematopoietic tissues (fibroblasts and lung epithelial cells) as well in hematopoietic cells (peripheral blood mononuclear cells (PBMCs)). Genome-wide gene expression analysis demonstrated a profound loss of type I and III IFNs in PBMCs infected with influenza virus.
GSE66545 ImmunoHuman IBD 26 2 Histology in the mesentery pointed to altered blood vessels. This experiment was designed to define the differences in gene expression in vessels from Crohn's disease versus controls. Crohn's disease was separately evaluated in inflamed (central disease) areas and in adjacent noninflamed areas.
GSE66573 ImmunoHuman 2015Q2 14 1 It is fundamentally unknown how normal cellular processes or responses to extracellular stimuli may invoke polyadenylation and degradation of ncRNA substrates or if human disease processes exhibit defects in polyadenylation of ncRNA substrates as part of their pathogenesis. Our results demonstrate that mononuclear cells from subjects with relapsing-remitting multiple sclerosis (RRMS) exhibit pervasive increases in levels of polyadenylated ncRNAs including Y1 RNA, 18S and 28S rRNA, and U1, U2, and U4 snRNAs and these defects are unique to RRMS. Defects in expression of both Ro60 and La proteins in RRMS appear to contribute to increased polyadenylation of ncRNAs. Further, IFN-ß1b, a common RRMS therapy, restores both Ro60 and La levels to normal as well as levels of polyadenylated Y1 RNA and U1 snRNA suggesting that aberrant polyadenylation of ncRNA substrates may have pathogenic consequences.
GSE66635 ImmunoHuman Arthritis 24 1 Background: Meniscus tears are the most common injury in the knee and are associated with an increased risk of osteoarthritis (OA). The molecular profile of knees with meniscus tears is not well-studied. Therefore, to advance our understanding of the early response of the knee to injury, we compared the gene expression profile of meniscus and articular cartilage within the same knees following meniscus injury. Hypothesis/Purpose: To identify differences between the molecular signatures of meniscus and articular cartilage from knees with intact articular cartilage undergoing arthroscopic partial meniscectomy. Study Design: Descriptive laboratory study Methods: Patients (n=12) with a known isolated medial meniscus tear without any knee chondrosis or radiographic OA were consented prior to surgery. During arthroscopic partial meniscectomy, a sample of their injured meniscus and a sample of their articular cartilage off the medial femoral condyle were procured. The transcriptome signatures, as measured through Affymetrix microarray, were compared between the two tissues and underlying biological processes were explored computationally.\r\nResults: 3566 gene transcripts were differentially expressed between meniscus and articular cartilage. Gene transcripts down-regulated in articular cartilage were associated with extracellular matrix organization, wound healing, cell adhesion, and chemotaxis. Gene transcripts up-regulated in articular cartilage were associated with blood vessels morphogenesis and angiogenesis. Examples of individual genes with significant differences in expression between the two tissues include IBSP (23.76 fold; P < 0.001), upregulated in meniscus, and TREM1 (3.23 fold; P = 0.006), upregulated in meniscus. Conclusion: The meniscus and articular cartilage have distinct gene expression profiles in knees with meniscus tears and intact articular cartilage.
GSE66763 ImmunoHuman MultipleSclerosis 14 2 Myelin-reactive T cells have been identified in patients with multiple sclerosis (MS) and healthy subjects with comparable frequencies, but the contribution of these autoreactive T cells to disease pathology remains unknown. A total of 13,324 T cell libraries generated from blood of 23 patients and 22 healthy controls were interrogated for reactivity to myelin antigens. Libraries derived from CCR6+ myelin-reactive T cells from patients with MS exhibited significantly enhanced production of IFN-gamma, IL-17, and GM-CSF compared to healthy controls. Single-cell clones isolated by MHC/peptide tetramers from CCR6+ T cell libraries also secreted more pro-inflammatory cytokines while clones isolated from controls secreted more IL-10. The transcriptomes of myelin-specific CCR6+ T cells from patients with MS were distinct from those derived from healthy controls, and of note, were enriched in Th17-induced experimental autoimmune encephalitis (EAE) gene signatures and gene signatures derived from Th17 cells isolated other human autoimmune diseases. These data, although not casual, imply that functional differences between antigen specific T cells from MS and healthy controls is fundamental to disease development and support the notion that IL-10 production from myelin-reactive T cells may act to limit disease progression, or even pathogenesis.
GSE66824 ImmunoHuman 2015Q2 66 3 Patients with chronic illnesses such as Irritable Bowel Syndrome (IBS) or Inflammatory Bowel Disease (IBD) often have reduced quality of life. IBS is characterized by abdominal pain/discomfort associated with altered bowel function, such as diarrhea or constipation, without gross structural changes or inflammation [1]; IBD is characterized by gross inflammation in the gastrointestinal (GI) tract which can result in symptoms such as abdominal pain, cramping, diarrhea and bloody stools. IBS and IBD can profoundly affect quality of life and are influenced by stress and resiliency.The impact of mind-body interventions (MBIs) on IBS and IBD patients has not previously been examined. In this study IBS and IBD patients were enrolled in a 9-week relaxation response based mind-body group intervention (RR-MBI), focusing on elicitation of the RR and cognitive skill building. We performed Peripheral blood transcriptome analysis to identify genomic correlates of the RR-MBI.
GSE66972 ImmunoHuman NormalControl 20 1 Th17 cells act as the first line of defense against pathogens at mucosal surfaces. Their paucity during HIV infection causes disease progression.\r\nHere, we reveal the existence of two new CCR6+CD161+ subsets, CCR4-CXCR3- (DN; double negative) and CCR4+CXCR3+ (DP; double positive), expressing typical Th17 transcripts (e.g., ROR?t, RORa, PTPN13, ARNTL), C. albicans specificity, and exhibiting Th17-lineage commitment versus flexibility.
GSE6710 ImmunoHuman Psoriasis 26 1 Biopsies from uninvolved and from lesional skin of 13 patients with plaque-type psoriasis. Based on paired samples, 179 genes were more than 2-fold differentially expressed in lesional skin.
GSE67196 ImmunoHuman ALS 53 4 Increasing evidence suggests that defective RNA processing contributes to the development of amyotrophic lateral sclerosis (ALS). This may be especially true for ALS caused by a repeat expansion in C9orf72 (c9ALS), in which the accumulation of RNA foci and dipeptide-repeat proteins are expected to modify RNA metabolism. We report extensive alternative splicing (AS) and alternative polyadenylation (APA) defects in the cerebellum of c9ALS cases (8,224 AS, 1,437 APA), including changes in ALS-associated genes (e.g. ATXN2 and FUS), and cases of sporadic ALS (sALS; 2,229 AS, 716 APA). Furthermore, hnRNPH and other RNA-binding proteins are predicted as potential regulators of cassette exon AS events for both c9ALS and sALS. Co-expression and gene-association network analyses of gene expression and AS data revealed divergent pathways associated with c9ALS and sALS.
GSE67250 ImmunoHuman IBD 6 1 Tissue fibrosis is a serious complication of Crohn’s disease (CD) as well as of a variety of other complex, chronic pathologies. Understanding the underlying pathophysiology of tissue fibrosis is crucial for the development of tissue-specific prevention and interventional treatment strategies. To identify molecular states specific to fibrotic disease, we employed deep sequencing to define the genome-wide DNA methylome and the whole transcriptome of purified human intestinal fibrotic fibroblasts (HIFs) isolated from the colon of patients with fibrotic CD. Integration of this information, via computational tools, identified candidate molecular interactions that could lead to fibrosis pathology. Our definition of a genome-wide fibrosis-specific DNA methylome provides a new paradigm for understanding mechanisms of pathological gene expression that lead to intestinal fibrosis and may have relevance to fibrogenesis in other organs.
GSE6731 ImmunoHuman IBD 36 4 Ulcerative colitis (UC) and Crohn’s disease (CD) are inflammatory bowel diseases (IBD) with variable, overlapping clinical features and complex pathophysiologies. To identify pathogenic processes underlying these disease subtypes, using single endoscopic pinch biopsies to estabolish 36 expression profiles, we elucidated gene expression patterns of active and inactive areas of UC and CD, and compared these to infectious colitis and healthy controls.
GSE67333 ImmunoHuman AD 8 1 Our data provide a comprehensive list of transcriptomics alterations and warrant holistic approach including both coding and non-coding RNAs in functional studies aimed to understand the pathophysiology of LOAD
GSE67338 ImmunoHuman MultipleSclerosis 6 1 Neuroblastoma is an embryonal tumor which originates from neural crest progenitor cells that fail to differentiate along their predefined route to sympathetic neurons or sympatho-adrenergic adrenal cells. It is the most common extracranial tumor of childhood and accounts for 15% of all childhood cancer deaths. Especially patients suffering from high grade or relapsed neuroblastoma have poor outcome in spite of aggressive treatment regimens including autologous stem cell transplantation. Those patients are in urgent need of additional effective therapies which demands the development of targeted approaches. Dihydroorotatedehydrogenase (DHODH) is the fourth enzyme of the pyrimidine synthesis pathway which oxidizes dihydroorotate to orotate. In recent past it became a potential drug target for cancer treatment because of its keyrole in processing essential pyrimidine nucleotides. On the basis of the existing data, functional inhibition of DHODH is considered to be promising therapeutic option for several tumor entities like advanced colorectal, breast or lung-cancers. Leflunomide is an established drug in treatment of the autoimmune diseases rheumatoid arthritis and multiple sclerosis. In the liver Leflunomide becomes converted to its active metabolite called Teriflunomide, which inhibits the activity of DHODH directly. In recent times Leflunomide is also used for therapy against the Cytomegalovirus and the BK virus. Also for Melanoma was shown recently a decreased growth rate due to Leflunomide treatment in a zebrafish and a mouse model. As Melanoma is a malignant tumor of the skin, which derives also from neural crest progenitor cells, a coherent investigation of effictivity of Leflunomide in neuroblastoma celllines showed first promising results. The aim of our study was to reanalyse the effectivity of Leflunomide in Neuroblastoma and to shed further light in its biological mode of action.
GSE67472 ImmunoHuman 2015Q2 105 2 Airway epithelial brushings were obtained for microarray analysis by research bronchoscopy in 62 subjects with mild-to-moderate asthma not on inhaled steroids and 43 healthy controls. Asthma subjects were stratified into 2 subgroups, Th2 high and Th2 low asthma, based on their expression of a three-gene signature of Type 2 inflammation: POSTN, SERPINB2, and CLCA1.
GSE67596 ImmunoHuman Arthritis 72 4 The polyarticular and oligoarticular forms of juvenile idiopathic arthritis are classified as distinct entities. At the same time, many children who present with an oligoarticular phenotype eventually evolve to a polyarticular disease pattern, suggesting that the phenotypes might share with overlapping molecular mechanisms. Using gene expression microarrays, we found that 14 genes in neutrophils and 55 genes in PBMC shows common patterns of differential expression when children with active oligoarticular and polyarticular JIA were compared with healthy controls. These results demonstrate that there are commonalities between oligoarticular and polyarticular JIA that suggest overlapping immune mechanisms.
GSE67785 ImmunoHuman Psoriasis 28 1 Background: Psoriasis is a chronic disease characterized by the development of scaly red skin lesions and possible co-morbid conditions. The psoriasis lesional skin transcriptome has been extensively investigated, but mRNA levels do not necessarily reflect protein abundance. Methods: Lesional (PP) and uninvolved (PN) skin samples from 14 patients were analyzed using high-throughput complementary DNA sequencing (RNA-seq) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: We identified 4122 differentially expressed genes (DEGs) along with 748 differentially expressed proteins (DEPs). Global shifts in mRNA were modestly correlated with changes in protein abundance (r = 0.40). We identified similar numbers of increased and decreased DEGs, but 4-fold more increased than decreased DEPs. Ribosomal subunit and translation proteins were elevated within lesions, without a corresponding shift in mRNA expression (RPL3, RPS8, RPL11). We identified 209 differentially expressed genes/proteins (DEGPs) with corresponding trends at the transcriptome and proteomic levels. Most DEGPs were similarly altered in at least one other skin disease. Psoriasis-specific and non-specific DEGPs had distinct cytokine-response patterns, with only the former showing disproportionate induction by IL-17A in cultured keratinocytes. Conclusions: Our findings reveal global imbalance between the number of increased and decreased proteins in psoriasis lesions, consistent with heightened translation. This effect could not have been discerned from mRNA profiling data alone. We have also identified high-confidence DEGPs and shown that only those most specific to psoriasis are enriched with IL-17A targets.
GSE67940 ImmunoHuman Asthma 104 2 Bronchial Epithelial Cells were isolated processed as described (Chu et al., 2002 and Zhao et al., 2011). The objective of the study was to identify differentially expressed genes between normal control (NC), mild-moderate asmathic (notSA) and severe asthmatic (SA) patients. For demographics data, contact Dr. Sally Wenzel (wenzelse@upmc.edu)
GSE68310 ImmunoHuman Influenza 880 1 The purpose of the study was to assess the patterns of global gene expression in peripheral blood cells and uncover the complex dynamics of host response to ARIs such as pandemic H1N1. To understand the molecular bases and network orchestration of host responses, we prospectively enrolled 1610 healthy adults in the fall of 2009 and 2010, followed the subjects with influenza-like illness (N=133) for 3 weeks, and examined changes in their peripheral blood gene expression. We discovered distinct phases of the host response spanning 6 days after infection, and identified genes that differentiate influenza from non-influenza virus infection. We examined pre- and post-infection anti-influenza antibody titers defining novel gene expression correlates.
GSE68378 ImmunoHuman BI Rush 10 4 Purpose: Oxygen (O2) levels in cell culture conditions is typically 2-5 fold higher than the physiological O2 levels that most tissues experience in vivo. The ambient atmospheric O2 (21%) is known to induce cell proliferation defects and cellular senescence in stem cell and primary cell cultures. Therefore, culturing these cells under lower O2 levels (2-9%) is currently a standard practice. However, the non-cancerous immortalized cells and cancer cells, which evade cellular senescence are normally cultured under 21% O2 levels and the effects of higher O2 levels on these cells are not fully understood.\r\nMethods: Gene expression (RNA seq transcriptomics) analysis of immortalized human bronchial epithelial (BEAS-2B) cells cultured at ambient 21% O2 and lower 10% O2 levels for 3 days and 3 weeks. Further the beneficial effects of cuturing cells under lower oxygen tension is evalulated\r\nResults: Our results show NF-?B/RelA mediated activation of pro-inflammatory cytokines as a major outcome of cells being cultured 21% O2. Moreover, we demonstrate increased RelA binding at the NF-?B1/RelA target gene promoters at 21% O2. Interestingly, contrary to cells cultutred at 21% O2, external stress induced by H2O2 exposure did not induce inflammatory response in cells grown at 10% O2, suggesting increased ability to handle external stress in cells cultured at lower O2 levels.
GSE68605 ImmunoHuman ALS 11 1 Objective: An intronic GGGGCC-repeat expansion of C9ORF72 is the most common genetic variant of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The mechanism of neurodegeneration is unknown, but a direct effect on RNA processing mediated by RNA foci transcribed from the repeat sequence has been proposed.\r\nResults: Gene level analysis revealed a number of differentially expressed networks and both cell types exhibited dysregulation of a network functionally enriched for genes encoding ‘RNA splicing’ proteins. There was a significant overlap of these genes with an independently generated list of GGGGCC-repeat protein binding partners. At the exon level, in lymphoblastoid cells derived from C9ORF72-ALS patients splicing consistency was lower than in lines derived from non-C9ORF72 ALS patients or controls; furthermore splicing consistency was lower in samples derived from patients with faster disease progression. Frequency of sense RNA foci showed a trend towards being higher in lymphoblastoid cells derived from patients with shorter survival, but there was no detectable correlation between disease severity and DNA expansion length.\r\nSignificance: Up-regulation of genes encoding predicted binding partners of the C9ORF72 expansion is consistent with an attempted compensation for sequestration of these proteins. A number of studies have analysed changes in the transcriptome caused by C9ORF72 expansion, but to date findings have been inconsistent. As a potential explanation we suggest that dynamic sequestration of RNA processing proteins by RNA foci might lead to a loss of splicing consistency; indeed in our samples measurement of splicing consistency correlates with disease severity.
GSE68765 ImmunoHuman IBD 24 3 Analysis examining the effect of the Crohn's disease-associated ATG16L1 polymorphism on the responses to stimulation components derived from various bacteria classes.
GSE69026 ImmunoHuman Influenza 61 12 The purpose is to obtain samples for mRNA, miRNA, proteomics, lipidomics, metabolomics, and histopathology analysis in human Calu-3 cells infected with WT A/Anhui/1/2013 (H7N9; 'AH1'), AH - NS1-103F/106M, and AH1 - 691 (ferret adapted virus).
GSE69239 ImmunoHuman BI Rush 20 0 To elucidate the transcriptional ‘landscape’ that regulates human lymphoid commitment during postnatal life, we used RNA sequencing to assemble the long non-coding transcriptome across human bone marrow and thymic progenitor cells spanning the earliest stages of B lymphoid and T lymphoid specification. Over 3,000 genes encoding previously unknown long non-coding RNA (lncRNAs) were revealed through the analysis of these rare populations. Lymphoid commitment was characterized by lncRNA expression patterns that were highly stage specific and were more lineage specific than those of protein-coding genes. Protein-coding genes co-expressed with neighboring lncRNA genes showed enrichment for ontologies related to lymphoid differentiation. The exquisite cell-type specificity of global lncRNA expression patterns independently revealed new developmental relationships among the earliest progenitor cells in the human bone marrow and thymus.
GSE69762 ImmunoHuman IBD 30 3 The entire small intestine was obseved by balloon endoscopy. Biopsy specimens were taken from jejunum, ileum and colon, respectively.
GSE69764 ImmunoHuman PulmonaryFibrosis 6 1 Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease. Although the pathogenesis is poorly understood, evidence suggests that genetic and epigenetic alterations, such as DNA methylation, may play a key role. We used microarrays to see the gene expression in IPF fibroblasts after demethylation agent 5'-azacytidine treatment.
GSE69818 ImmunoHuman COPD 70 1 Comparison of emphysema vs non emphysema COPD lung tissue expression
GSE70544 ImmunoHuman Inflammation 12 2 To identify RNA transcripts involved in acute and chronic renal epithelial injury, we performed unbiased whole transcriptome profiling of human proximal tubular epithelial cells (PTECs) in hypoxic and inflammatory conditions. RNA sequencing (RNA-seq) revealed that the protein-coding and noncoding transcriptomic landscape differed between hypoxia-stimulated and cytokine-stimulated human PTECs.
GSE71220 ImmunoHuman COPD 617 2 Background: COPD is currently the fourth leading cause of death worldwide and predicted to rank third by 2020. Statins are commonly used lipid lowering agents with documented benefits on cardiovascular morbidity and mortality, and have also been shown to have pleiotropic effects including anti-inflammatory and anti-oxidant activity. Objective: Identify a gene signature associated with statin use in the blood of COPD patients, and identify molecular mechanisms and pathways underpinning this signature that could explain any potential benefits in COPD. Methods: Whole blood gene expression was measured on 168 statin users and 452 non-users from the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study. Gene expression was measured using the Affymetrix Human Gene 1.1 ST microarray chips. Factor Analysis for Robust Microarray Summarization (FARMS) was used to process the expression data and to filter out non-informative probe sets. Differential gene expression analysis was undertaken using the Linear Models for Microarray data (Limma) package adjusting for propensity score and employing a surrogate variable analysis. Similarity of the expression signal with published gene expression profiles was performed in ProfileChaser. Results: 18 genes were differentially expressed between statin users and non-users at a false discovery rate of 10%. Top genes included LDLR, ABCA1, ABCG1, MYLIP, SC4MOL, and DHCR24. The 18 genes were significantly enriched in pathways and biological processes related to cholesterol homeostasis and metabolism, and were enriched for transcription factor binding sites for sterol regulatory element binding protein 2 (SREBP-2). The resulting gene signature showed correlation with Huntington disease, Parkinson’s disease and acute myeloid leukemia. Conclusion: Statins gene signature was not enriched in any pathways related to respiratory diseases, beyond the drug’s effect on cholesterol homeostasis.
GSE71351 ImmunoHuman PulmonaryFibrosis 12 2 Analysis of Idiopathic pulmonary fibrosis (IPF) at gene expression level. The hypothesis tested in the present study was that Epigenetic mechanisms are likely to be associated with pathogenesis in IPF. To determine the DNA methylation change, and their effects on gene expression, we compared microarray data of DNA methylation and RNA expression. Results provide that among the genes whose DNA methylation status and RNA expression were both significantly altered between IPF-rapid and normal controls.
GSE71595 ImmunoHuman Arthritis 14 2 Through RNA sequencing of CD4+ Tmemory/effector cells derived from the synovium of JIA patients and healthy controls, we analyzed the JIA gene expression signature. Treatment of autoinflammatory site-derived patient T cells with the BET-inhibitor JQ1 inhibited immune-related super-enhancers and preferentially reduced disease-associated gene expression, including cytokine-related processes.
GSE71634 ImmunoHuman MultipleSclerosis 40 1 This experiment was carried out in the context of a pharmacogenetic study of long-term (4-year follow-up) response to Interferon-beta treatment in two cohorts of Italian Multiple Sclerosis patients, to identify genetic variants (SNPs) that may influence response to IFN-beta. We integrated results from meta-analysis of the two cohorts with gene expression profiling of IFNß stimulated PBMCs from 20 healthy controls and eQTL analyses, to look at possible enrichment of IFN-beta induced genes with genes mapped by top-ranking meta-analyzed SNPs.
GSE71709 ImmunoHuman PulmonaryFibrosis 9 1 Mutations in the poly(A) ribonuclease (PARN) gene cause telomere diseases including familial idiopathic pulmonary fibrosis (IPF) and dyskeratosis congenita (DC)1,2, but how PARN deficiency impacts telomere maintenance is unclear. Here, using somatic cells and induced pluripotent stem (iPS) cells from DC patients with PARN mutations, we show that PARN is required for the 3' end maturation of the telomerase RNA component (TERC). Patient cells as well as immortalized cells in which PARN is disrupted show decreased levels of TERC. Deep sequencing of TERC RNA 3' termini reveals that PARN is required for removal of posttranscriptionally acquired oligo(A) tails that target nuclear RNAs for degradation. Diminished TERC levels and the increased oligo(A) forms of TERC are normalized by restoring PARN, which is limiting for TERC maturation in cells. Our results reveal a novel role for PARN in the biogenesis of TERC, and provide a mechanism linking PARN mutations to telomere diseases.
GSE71730 ImmunoHuman IBD 47 2 The complex milieu of inflammatory mediators associated with many diseases is often too dilute to directly measure in the periphery, necessitating development of more sensitive measurements suitable for mechanistic studies, earlier diagnosis, guiding selection of therapy, and monitoring interventions. Previously, we determined that plasma of recent-onset (RO) Type 1 diabetes (T1D) patients induce a proinflammatory transcriptional signature in fresh peripheral blood mononuclear cells (PBMC) relative to that of unrelated healthy controls (HC). Here, using an optimized cryopreserved PBMC-based protocol, we apply this approach to inflammatory bowel disease by examining groups of Crohn's disease (CD) and ulcerative colitus (UC) patients. The induced plasma induced signatures are compared to those of Type 1 diabetes patients (RO T1D) as well as unrelated healthy controls (uHC).
GSE71766 ImmunoHuman Influenza 186 27 Human rhinovirus and influenza virus infections of the upper airway lead to colds and the flu and can trigger exacerbations of lower airway diseases including asthma and chronic obstructive pulmonary disease. Despite modest advances in the diagnosis and treatment of infections by these viruses, novel diagnostic and therapeutic targets are still needed to differentiate between the cold and the flu, since the clinical course of influenza can be severe while that of rhinovirus is usually more mild.\r\nIn our investigation of influenza and rhinovirus infection of human respiratory epithelial cells, we used a systems approach to identify the temporally changing patterns of host gene expression from these viruses. After infection of human bronchial epithelial cells (BEAS-2B) with rhinovirus, influenza virus or co-infection with both viruses, we studied the time-course of host gene expression changes over three days. From these data, we constructed a transcriptional regulatory network model that revealed shared and unique host responses to these viral infections such that after a lag of 4-8 hours, most cell host responses were similar for both viruses, while divergent host cell responses appeared after 24-48 hours. The similarities and differences in gene expression after epithelial infection of rhinovirus, influenza virus, or both viruses together revealed qualitative and quantitative differences in innate immune activation and regulation. These differences help explain the generally mild outcome of rhinovirus infections compared to influenza infections which can be much more severe.
GSE72073 ImmunoHuman PulmonaryFibrosis 8 1 Idiopathic pulmonary fibrosis (IPF) is a progressive lethal interstitial lung disease of unkown etiology with limited effective therapies. The pathogenic mechanisms of IPF remain unkown. Emerging evidences indicate that abnormal behaviors of fibroblasts in IPF are associated with a variety of genetic alterations and aberrant reactivation of developmental signaling pathways.\r\nWe compared gene expression profiles in fibrotic lung tissues from IPF patients and normal lung tissues from patients with primary spontaneous pneumothorax using cDNA microarray to examine the mechnisms involved in the pathogenesis of IPF.
GSE7216 ImmunoHuman Psoriasis 25 8 Normal human epidermal keratinocytes (NHEK) from neonatal foreskin were cultured in serum-free EpiLife medium with human KC growth supplement (0.2% bovine pituitary extract (v/v), 5ug bovine insulin, 5ug/ml bovine transferrin, 0.5ng/ml human EGF, and 0.18 ug/ml hydrocortisone) from Cascade Biologics. Cultures were treated with recombinant cytokines from R&D Systems. J Immunol. 2007 Feb 15;178(4):2229-40.
GSE72163 ImmunoHuman IBD 36 2 Objective: Cigarette smoking ameliorates ulcerative colitis (UC) and aggravates Crohn’s disease (CD). Cigarette smoke suppresses inflammation-induced apoptosis in intestinal epithelial cells (DLD-1), which may explain its protective effect in UC. Here, we performed transcriptome profiling of cigarette smoke extract (CSE)-exposed DLD-1 and Jurkat cells (T-lymphocytes) and related this to UC susceptibility genes with protective functions in the intestinal epithelium.\r\nDesign: CSE-regulated genes in DLD-1 and Jurkat cells were identified by Illumina microarrays and compared to genes in UC susceptibility loci. Colon biopsies were analyzed by immunohistochemistry for cell-specific expression of HSPA6. CSE-induced gene expression was analyzed by Q-PCR, Western blotting and immunofluorescence microscopy. Protein (HSPA6/Bcl-XL) interactions were analyzed by immunoprecipitation.\r\nResults: CSE changed the expression of 536 and 2,560 genes in DLD-1 and Jurkat cells, respectively. The “response to unfolded protein” was one of the most significantly affected gene sets with prominent induction (20.3-fold) of heat shock protein A6 (HSPA6). Six CSE-induced genes in DLD-1 cells were located in UC-susceptibility loci, including HSPA6 (rs1801274). HSPA6 is highly expressed in the human colonic epithelium. CSE caused a dose-dependent strong (>100-fold at 30% CSE for 6 hours), but transient induction of HSPA6 mRNA and protein in DLD-1 cells. HSPA6 co-immune precipitated with anti-apoptotic Bcl-XL, protein levels of which were increased while mRNA levels were unchanged.\r\nConclusion: HSPA6 is a cigarette smoke-induced UC-susceptibility gene. The HSPA6 risk locus is associated with decreased HSPA6 expression. HSPA6 provides epithelial protection by stabilizing anti-apoptotic Bcl-XL, thereby contributing to the beneficial effect of cigarette smoking in UC.
GSE72258 ImmunoHuman Arthritis 12 2 The variant rs26232, in the first intron of the C5orf30 locus, has recently been associated with both risk of developing rheumatoid arthritis (RA) and severity of tissue damage. The biological activities of human C5orf30 are unknown, and neither the gene nor protein show significant homology to any other characterized human sequences. The C5orf30 gene is present only in vertebrate genomes with a high degree of conservation implying a central function in these organisms. Here we report that C5orf30 is highly expressed in the synovium of RA patients compared with control synovial tissue, and that it is predominately expressed by synovial fibroblast (RASF) and macrophages in the lining and sublining layer of the tissue. These cells play a central role in the initiation and perpetuation of RA and are implicated in cartilage destruction. RASFs lacking C5orf30 exhibit increased cell migration and invasion in vitro and gene-profiling following C5orf30 inhibition confirmed upregulation of genes involved in cell migration, adhesion, angiogenesis, and immune and inflammatory pathways. Importantly, loss of C5orf30 contributes to the pathology of inflammatory arthritis in vivo, since inhibition of C5orf30 in the collagen-induced arthritis model markedly accentuated joint inflammation and tissue damage. Our study reveal C5orf30 to be a novel negative regulator of tissue damage in RA and this may act by modulating the autoaggressive phenotype that is characteristic of RASFs.\r\nRheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease that affects synovial joints. A key characteristic of RA is hyperplasia of fibroblast-like synoviocytes (FLS) which develop a stable, auto-aggressive phenotype that augments tissue destruction. It is unknown how this phenotype is stably maintained; however, epigenetic changes have been implicated. Histone deacetylation is one proposed method; a process controlled by histone deacetylases (HDACs). However, there have recently been reports publishing conflicting data regarding the expression of HDACs in RA synovium and FLS. The objective of this thesis is to determine the role of HDACs in regulating the auto-aggressive phenotype of RA through studies in FLS and in mice. Real time-quantitative PCR was used to assess the levels of HDAC1-11 in RA compared to osteoarthritis (OA) FLS. Immunohistochemistry and western blotting were used to assess protein expression of HDAC1 in RA and OA synovial tissue and FLS. HDAC1 was found to be overexpressed in RA compared to OA. HDAC1 was knocked down in RA FLS, then cell proliferation, migration and invasion were assessed by using tritiated thymidine, a scratch assay and a Matrigel invasion assay respectively. All three functions were significantly reduced following HDAC1 knockdown. An Illumina BeadChip (47,000 transcripts) was used to analyse global gene expression changes after knockdown. This revealed significant gene changes in important functional clusters, such as proliferation and migration. HDAC1 knockout is embryonic lethal in mice, so the in vivo role of HDAC1 was investigated in a mouse model of collagen-induced arthritis (CIA) using in vivo siRNAs. Clinical scores of CIA were measured daily and HDAC1 knockdown mice showed a significantly reduced clinical score compared to controls, comparable to dexamethasone-treated mice. The bones were analysed using a microCT scanner and histology. Knocking down HDAC1 showed reduced bone erosion, joint inflammation and cartilage degradation compared to controls. Overall, this study shows that HDAC1 is dysregulated in RA and it has a significant role in the autoaggressive phenotype shown in RA FLS and collagen-induced arthritis. The novel data shown in this thesis demonstrates that inhibiting HDAC1 may provide a powerful new target for treating RA.
GSE72396 ImmunoHuman Psoriasis 4 1 Psoriasis is an inflammatory skin disease and the exact pathogenesis has not been fully illuminated yet. It has been demonstrated that interleukin-22 (IL-22) plays a significant role in the pathogenesis of psoriasis.\r\nOur study aimed to explore the role of IL-22 and its target miRNAs in pathogenesis of psoriasis.
GSE72420 ImmunoHuman SLE 133 1 This SuperSeries is composed of the SubSeries listed below.
GSE72509 ImmunoHuman SLE 117 1 RNA-seq of systemic lupus erythematosus (SLE) whole blood and healthy controls to determine the gene expression changes in these patients.
GSE72780 ImmunoHuman IBD 9 1 Inflammatory Bowel Diseases are associated with marked alterations of IECs with a subsequent loss of barrier function.\r\nTo identify alterations in signaling pathways in intestinal epithelium upon inflammation, we analyzed the transcriptome of IECs from patients suffering from Crohn’s disease.
GSE72819 ImmunoHuman IBD 73 2 RNA sequencing was performed on RNA isolated from baseline biopsies from UC patients enrolled in the Phase II EUCALYPTUS study of etrolizumab. Gene expression differences were identified in a subset of anti-TNF naïve patients that achieved clinical remission at 10 weeks in response to etrolizumab.
GSE73189 ImmunoHuman PulmonaryFibrosis 12 2 We report abonormally expressed genes of idiopathic interstitial pneumonia by RNA-seq analysis. BMP3 was found down-regulated in idiopathic intestital pneumonia patients, and it closely correlated with pathogenesis of disease. The role of BMP3 in advancement of idiopathic interstitial pneumonia was verified by a series of experiments.
GSE73608 ImmunoHuman MultipleSclerosis 85 3 Interferon (IFN) beta-1a is an approved treatment for relapsing remitting multiple sclerosis (RRMS) and has been examined for use in secondary progressive multiple sclerosis (SPMS). However, no information regarding blood transcriptional changes induced by IFN treatment in SPMS patients is available.\r\nOur aim was to identify a subgroup of SPMS patients presenting a gene expression signature similar to that of RRMS patients who are clinical responders to IFN treatment.
GSE7368 ImmunoHuman Asthma 6 1 Background: A subset of asthmatics does not respond to steroid therapy and therefore is at risk for escalation of disease severity. The cause of corticosteroid resistant (CR) asthma is unknown. Gene microarray technologies have the potential to substantiate new hypotheses regarding the etiology of corticosteroid resistance.\r\nMethods: Gene microarray analysis was performed with bronchoalveolar lavage (BAL) cells of CR and corticosteroid sensitive (CS) asthmatics. Increased gene expression was verified with real time PCR and at the protein level by ELISA.\r\nFindings: Microarray analyses demonstrated significantly higher levels (over two-fold increase, p<0.05) of TNF-alpha, IL-1alpha, IL-1beta, IL-6, CXCL1, CXCL2, CXCL3, CXCL8 (IL-8), CCL3, CCL4, CCL20 gene expression in BAL cells of CR than CS asthmatics. These findings, confirmed by RT-PCR in additional BAL samples, were consistent with classical macrophage activation by bacterial products. In contrast, markers of alternatively-activated macrophages, Arginase I and CCL24, were decreased in CR asthmatics. Genes associated with activation of the LPS signaling pathway (EGR1, DUSP2, MAIL, TNFAIP3) were significantly elevated in CR BAL samples (p<0.05). CR asthmatics had significantly higher amounts (1444.0±457.3 pg per mg of total protein) of LPS in BAL fluid than CS asthmatics (270.5±216.0 pg; p<0.05). Prolonged exposure to LPS induced functional steroid resistance to dexamethasone (DEX) in normal monocytes, demonstrated by persistently elevated IL-6 levels in the presence of DEX. Interpretation: Classical macrophage activation and induction of LPS signaling pathways along with high endotoxin levels detected in BAL fluid from CR asthmatics suggest that LPS exposure may contribute to CR asthma.
GSE73721 ImmunoHuman BasicScience 41 0 Astrocytes were purified from fetal and adult human brain tissue using an immunopanning method with the HepaCAM antibody. Samples were taken from otherwise 'healthy' pieces of tissue, unless otherwise specified.
GSE73754 ImmunoHuman Arthritis 72 2 Male AS patients have an elevated Th17 cell frequency vs. female AS patients (Gracey et al, Arthritis and Rheumatology, 2015). This analysis was performed to further examine differences between male and female AS patients
GSE74075 ImmunoHuman Asthma 16 3 Consumption of a high fat meal can increase neutrophilic airway inflammation in asthma. This study investigates the molecular mechanisms driving airway neutrophilia following a high fat meal in asthma.
GSE74442 ImmunoHuman LungDisease 13 1 Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans Cell (LCH) and non-Langerhans (non-LCH) histiocytoses, respectively. The discovery of BRAFV600E mutations in ~50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of BRAFV600E-wildtype, non-LCH patients are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in BRAFV600E-wildtype, non-LCH patients. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of MAP2K1- and ARAF-mutated, non-LCH patients using MEK and RAF inhibitors, respectively, resulted in clinical efficacy demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders.
GSE74697 ImmunoHuman Psoriasis 52 2 In this study, we used RNA-sequencing to profile the long non-coding RNA (lncRNA) transcriptome in lesional skin from psoriasis patients before (PP) and after treatment (PT) with adalimumab and in normal skin from healthy individuals (NN). For this we sequenced total RNA from 18 psoriasis patients (before and after treatment) and 16 healthy controls. We created our own reference set of long non-coding RNAs by merging three long non-coding RNA reference data sets. The combined reference had 67,157 lncRNA transcripts with no overlaps. We identified differential expression of 971 lncRNAs between PP and NN, 157 between PP and PT, and 377 between PT and NN. Based on differentially expressed (DE) lncRNAs between PP and NN, we identified a molecular lncRNA signature that distinguishes psoriatic skin from healthy skin .
GSE74761 ImmunoHuman Alopecia 11 3 Alopecia areata (AA) is a prevalent disease associated with major emotional distress, and lacks effective, safe therapeutics for patients with extensive hair loss. This is the first report of hair regrowth with specific cytokine antagonism, in three patients with extensive hair loss ranging from 40% scalp involvement to alopecia universalis. Ustekinumab, an IL-12/23p40 antagonist that is highly effective in psoriasis, showed impressive ability to induce hair regrowth, coupled with suppression of inflammatory pathways and upregulation of hair keratins. Our report suggests that extensive AA is reversible using targeted treatments, opening the door for specific cytokine antagonism for this debilitating disease.
GSE74876 ImmunoHuman nomodel 8 0 Oxidative stress illustrates an imbalance between radical formation and removal. Frequent redox stress is critically involved in a variety of human pathologies including cancer, psoriasis, and chronic wounds. However, reactive species pursue a dual role being involved in signaling on the one hand and oxidative damage on the other. Using a HaCaT keratinocyte cell culture model, we here aimed at investigating the cellular and transcriptional response to periodic, low dose oxidative challenge over three months. Chronic redox stress was generated by frequent incubation with cold physical plasma treated cell culture medium. Using mRNA microarray technology, we found both acute ROS stress responses as well as numerous adaptions on the transcriptional level and over several weeks of redox challenge. This included an altered expression of 260 genes that function in inflammation and redox homeostasis, such as, signaling molecules, cytokines, and anti-oxidant enzymes. Apoptotic signaling was affected to a minor extend, especially in p53 down-stream targets. Strikingly, the anti-apoptotic heat shock protein HSP27 was strongly upregulated. These results suggest a variety of adaptive responses relating involved a number of cellular processes elicited by frequent redox stress over several months. They may help to better understand inflammatory responses in redox related diseases and possibly allow uncovering new biomarkers of ROS-stress.\r\nMicroarrays were used to analyze and investigate the biological effects of repeated exposure of cold physical plasma on human HaCaT keratinocytes. Using an argon plasma jet kinpen, regulated transcripts were analyzed and further described in Schmidt et al. (submittes): “Long-term exposure to cold plasma-generated ROS –an in vitro model for redox-related diseases of the skin”.
GSE7510 ImmunoHuman GVHD 8 2 Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for high-risk hematological malignancies, yet a major complication associated with this therapy is acute graft-versus-host disease (GVHD). Despite a well-defined pathophysiological mechanism, there are no definitive markers for predicting acute GVHD development or progression to advanced stages. In the current study, we enrolled four acute GVHD and four acute GVHD-free recipients of allogeneic HSCT and collected peripheral blood just prior to onset of clinical acute GVHD for analysis on Affymetrix GeneChip Human Genome U133 Plus 2.0 microarrays. We noted significant differences in expression of 1,658 genes between control and acute GVHD patients, based on an analysis of covariance (ANCOVA) by type of transplant, a pooled error estimate, and a false discovery rate (FDR) of 10%. In conclusion, we offer the first report of a preliminary molecular signature of acute GVHD in allogeneic HSCT patients.
GSE7524 ImmunoHuman Arthritis 6 0 The purpose of this study was (1) to identify novel genes involved in the pathogenesis of Rheumatoid Arthritis (RA) disease, which may provide additional targets for therapeutic intervention and (2) to examine the molecular mechanisms associated with the response to anti-TNF treatment. Microarray analysis of LPS-stimulated whole blood from RA patients pre and post anti-TNF treatment was conducted. This study identified 818 transcripts, differentially expressed in RA patients pre-treatment compared to non-RA control samples. While a number of these genes were associated with RA in previous studies, validating our data, a number of novel genes with possible functions in RA disease were also identified. The number of transcripts (1051) significantly altered post anti-TNF treatment indicates the impact of anti-TNF therapy on systemic gene expression. A number of these transcripts were confirmed to be altered in a larger patient group and may represent potential genetic markers of a patient’s clinical response to anti-TNF treatment.
GSE75343 ImmunoHuman Psoriasis 45 3 Scalp psoriasis shows a variable clinical spectrum and in many cases poses a great therapeutic challenge. However, it remains unknown whether the immune response of scalp psoriasis differs from understood pathomechanisms of psoriasis on other skin areas. We sought to determine the cellular and mollecular phenotype of scalp psoriasis by performing a comparative analysis of scalp vs skin using lesional and nonlesional samples from 20 Caucasian subjects with untreated moderate to severe psoriasis and significant scalp involvement, and 10 control subjects without psoriasis. Our results suggest that even in the scalp psoriasis is a disease of the inter-follicular skin. The immune mechanisms that mediate scalp psoriasis were found to be similar to those involved in skin psoriasis. However, the magnitude of dysregulation, number of differentially expressed genes, and enrichment of the psoriatic genomic fingerprinting were more prominent in skin lesions. Furthermore, the scalp transcriptome showed increased modulation of several gene-sets, particularly those induced by interferon-gamma, compared with skin psoriasis which was mainly associated with activation of TNF alpha/L-17/IL-22-induced keratinocyte response genes. We also detected differences in expression of gene-sets involving negative regulation, epigenetic regulation, epidermal differentiation, and dendritic cell or Th1/Th17/Th22-related T-cell processes.
GSE7568 ImmunoHuman Inflammation 25 2 The goal of the study was to identify the effects of TGF-beta on primary human macrophages maturated under different conditions.
GSE7621 ImmunoHuman PD 25 1 We used microarrays to detail the global program of gene expression underlying Parkinson's disease
GSE7669 ImmunoHuman Arthritis 12 1 mRNA expression levels in synovial fibroblasts in 6 rheumatoid arthritis patients versus 6 osteoarthritis patients.
GSE7753 ImmunoHuman Arthritis 47 1 Systemic Juvenile Idiopathic Arthritis (sJIA) has been strongly associated with macrophage activation syndrome (MAS). To better understand the pathogenesid of sJIA and to facilitate the search for MAS biomarkers, we examine gene expression profiles in untreated new onset sJIA.\r\n17 new onset sJIA patients were included in the study. 5 of the 17 patients showed evidence of subclinical MAS and 2 eventually developed overt MAS.
GSE7832 ImmunoHuman nomodel 20 0 Down-regulation of the Notch Differentiation Pathway in the Human Airway Epithelium in Normal Smokers and Smokers with Chronic Obstructive Lung Disease\r\nIn cigarette smokers, the toxic components of smoke place the epithelium under the constant stress of a variety of mechanisms of injury, with consequent modulation of airway epithelial regeneration and disordered differentiation. Based on the underlying hypothesis that these airway epithelial changes must involve quantitative changes in genes involved with the regulation of differentiation, we assessed the expression of the Notch pathway, a signaling pathway known to play a fundamental role in the embryonic lung as a gatekeeper for differentiation, in the small airway epithelium of non-smokers, normal smokers, and smokers with COPD. Microarray analysis demonstrated that 45 of the 55 Notch pathway-related genes are expressed in the human adult small airway epithelium and TaqMan quantitative PCR confirmed the expression of key genes in the pathway. TaqMan quantitative PCR analysis of the normal small airway epithelium demonstrated that Delta-like ligand 1 is the most highly expressed Notch ligand, Notch2 and 3 the most highly expressed receptor genes, and Hes1 the predominant downstream effector gene. TaqMan PCR was used to compare gene expression in nonsmokers vs healthy smokers vs smokers with COPD. The data show that some key genes in the ligands, receptors and downstream effectors in the Notch pathway are differentially expressed in smokers, with significant downregulation of a greater number of Notch-related genes in smokers with COPD compared to healthy smokers. These observations are consistent with the hypothesis that the Notch pathway, known to play an important role in lung morphogenesis, also likely plays a role in the adult human airway epithelium, with at least some of the Notch pathway gene expression dysregulated in association with smoking and its related disorder, COPD.
GSE7894 ImmunoHuman Asthma 29 1 Gene expression profiling was carried out on peripheral blood CD2+ leukocytes from 29 children with asthma. The primary research question is whether gene expression differs in individuals from high socioeconomic status environments vs low socioeconomic status environments.
GSE8052 ImmunoHuman Asthma 404 1 Asthma is caused by a combination of poorly understood genetic and environmental factors. We found multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P < 10-12. In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in EBV-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (P <10-22) in cis with transcript levels of ORMDL3, a member of a gene family that encode transmembrane proteins anchored in the endoplasmic reticulum. The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.
GSE8286 ImmunoHuman Arthritis 9 2 Macrophages play a critical role in the pathogenesis of many diseases, including rheumatoid arthritis, inflammatory bowel disease and atherosclerosis. Monocytes recruited into tissues from peripheral blood differentiate into macrophages. There is limited data concerning the global changes in the expression of genes during monocyte to macrophage, and how the patterns of change identify the mechanism contributing to differentiation or macrophage function. Employing the microarray technology, we examined the transcriptional profile of in vitro adherence-induced differentiation of primary human monocytes into macrophages. We found the significant up regulation of genes contributing to the functions of macrophage, including signature patterns defining the induction of genes contributing to immunity and defense; lipid, fatty acid and steroid metabolism; cell adhesion and; carbohydrate metabolism; amino acid metabolism and endocytosis. In contrast, a variety of transcription factors were down regulated during monocyte to macrophage differentiation, suggesting that transcriptional repression may be important for the transition from monocytes to macrophages. However, a limited number of transcription factors were up regulated, among these was C/EBPA, which may contribute to differentiation by regulating down stream genes, which a characteristic of differentiated macrophages. These observations suggest that examination of the transcriptional profile in monocytes and macrophages in patients may identify relevant therapeutic targets in diseases such as rheumatoid arthritis and atherosclerosis.
GSE8545 ImmunoHuman COPD 54 2 Despite overwhelming data that cigarette smoking causes chronic obstructive pulmonary disease (COPD), only a minority of chronic smokers are affected, strongly suggesting that genetic factors modify susceptibility to this disease. We hypothesized that there are individual variations in the response to cigarette smoking, with variability among smokers in expression levels of protective / susceptibility genes. Affymetrix arrays and TaqMan PCR were used to assess the variability of gene expression in the small airway epithelium obtained by fiberoptic bronchoscopy of 18 normal non-smokers, 18 normal smokers and 18 smokers with COPD.\r\nWe identified 201 probesets representing 150 smoking-responsive genes that were significantly up- or down-regulated, and assessed the coefficient of variation in expression levels among the study population. Variation was a reproducible property of each gene as assessed by different microarray probesets and realtime PCR and was observed in both normal smokers and smokers with COPD. There was greater individual variability in smokers with COPD than in normal smokers. The majority of these highly variable smoking responsive genes were in the functional categories of signal transduction, xenobiotic degradation, metabolism, transport, oxidant-related and transcription. A similar pattern of the same highly variable genes was observed in an independent data set.We propose that there is likely genetic diversity within this subset of genes with highly variable individual to individual responses of the small airway epithelium to smoking, and this subset of genes represent putative candidates for assessment of susceptibility/protection from disease for future gene-based epidemiological studies for the risk of smokers for COPD.
GSE8581 ImmunoHuman COPD 58 1 Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease with complex pathological features and largely unknown etiologies. Identification and validation of biomarkers for this disease could facilitate earlier diagnosis, appreciation of disease subtypes and/or determination of response to therapeutic intervention. To identify gene expression markers for COPD, we performed genome-wide expression profiling of lung tissue from 56 subjects using the Affymetrix U133 Plus 2.0 array. Lung function measurements from these subjects ranged from normal, un-obstructed to severely obstructed. Analysis of differential expression between cases (FEV1<70%, FEV1/FVC<0.7) and controls (FEV1>80%, FEV1/FVC>0.7) identified a set of 65 probe sets representing discrete markers associated with COPD. Correlation of gene expression with quantitative measures of airflow obstruction (FEV1 or FEV1/FVC) identified a set of 220 probe sets. A total of 31 probe sets were identified that showed evidence of significant correlation with quantitative traits and differential expression between cases and controls.
GSE8594 ImmunoHuman nomodel 10 0 Multiple sclerosis (MS) is a neuroinflammatory disease of the central nervous system (CNS) with a well documented genetic component. Significant advances in the identification of the genetic component of MS have yet to be realized. The recent success that genetical genomics has shown in the identification of new QTL in plants and mice hold significant promise that this method can now be systematically applied in humans. Encouraging results indicate that even normal variation in gene expression could be genetically encoded. Characteristic patterns of gene expression have been already identified in PBMC from MS patients, and a high-resolution map of the human genome is readily available. We are combining these two powerful sources of information towards the identification of the long-time elusive genetic component of MS. The study proposed herein of ten individuals is a pilot study to ensure that gene expression variation is detectable in selected samples from our lymphoblastoid cell line collection to warrart a larger genetical genomics study.\r\nPilot: Verify that there is sufficient variation in lymphoblastoid cell lines to warrant a full study.\r\nThe full study will have the following specific aim:\r\nTo explore and identify genomic regions responsible for the gene expression signature characteristic of multiple sclerosis patients.\r\nGene expression patterns across lymphoblastoid cell lines from MS patients are sufficiently variable.\r\nFollowing validation of the above hypothesis, the following hypothesis will be addressed in a full study:\r\nSome of the genetic determinants of multiple sclerosis can be identified through the combination of studying gene expression and genomic mutations associated with this gene expression.\r\nTen human lymphoblastoid cell line samples from our repository have been selected for this pilot study. Lymphoblastoid cell lines have been established by infection with the Epstein-Barr virus, and RNA has been isolated with the Rneasy kit (Qiagen, CA). RNA was quantitated using the RibogreenTM reagent (Molecular Probes, Eugene, OR) and its integrity was evaluated by agarose gel electrophoresis. BRB Arraytools, Bioconductor in R, and JMP Genomics (SAS Institute, Cary, NC) will be used to evaluate the expression variance of the samples by comparing them to already existing human microarray data.
GSE8608 ImmunoHuman COPD 6 3 In this study gene expression of monocyte-derived macrophages (MDM) from chronic obstructive pulmonary disease (COPD) patients and healthy subjects was investigated. MDM were treated with LPS, a combination of fine TiO2 and ultrafine Printex90 particles, or remained untreated.
GSE8650 ImmunoHuman Arthritis 246 6 Systemic onset Juvenile Idiopathic Arthritis (SoJIA) represents up to 20% of Juvenile Idiopathic Arthritis (JIA). We have previously reported that this disease is Interleukin 1 (IL1)-mediated, and that IL-1 blockade results in clinical remission in the majority of patients. The diagnosis of SoJIA, however, still relies on clinical findings as no specific diagnostic tests are available, which leads to delays in the initiation of specific therapy. To identify specific diagnostic markers, we analyzed gene expression profiles in 19 pediatric patients with SoJIA during the systemic phase of the disease (fever and/or arthritis), 25 SoJIA patients with no systemic symptoms (arthritis only or no symptoms), 39 healthy controls, 94 pediatric patients with acute viral and bacterial infections (available under GSE6269), 38 pediatric patients with Systemic Lupus Erythematosus (SLE), and 6 patients with a second IL-1 mediated disease known as PAPA syndrome. Statistical group comparison and class prediction identified genes differentially expressed in SoJIA patients compared to healthy children. These genes, however, were also changed in patients with acute infections and SLE. By performing an analysis of significance across all diagnostic groups, we generated a list of 88 SoJIA-specific genes (p<0.01 in SoJIA and >0.5 in all other groups). A subset of 12/88 genes permitted us to accurately classify an independent test set of SoJIA patients with systemic disease. We were also able to identify a group of transcripts that changed significantly in patients undergoing IL-1 blockade. Thus, analysis of transcriptional signatures from SoJIA blood leukocytes can help distinguishing this disease from other febrile illnesses and assessing response to therapy. Availability of accurate diagnostic markers for SoJIA patients may allow prompt initiation of effective therapy and prevention of long-term disabilities.
GSE8823 ImmunoHuman COPD 24 1 Mononuclear phagocytes play an important role in the removal of apoptotic cells by expressing cell surface receptors that recognize and remove apoptotic cells. Based on the knowledge that cigarette smoking is associated with increased lung cell turnover, we hypothesized that alveolar macrophages (AM) of normal cigarette smokers may exhibit enhanced expression of apoptotic cell removal receptor genes. AM obtained by bronchoalveolar lavage of normal non-smokers (n=11) and phenotypic normal smokers (n=13, 36 ± 6 pack-yr) were screened for mRNA expression of all known apoptotic cell removal receptors using Affymetrix HG-U133 Plus 2.0 chips with TaqMan RT-PCR confirmation. Of the 14 known apoptotic receptors expressed, only MER Tyrosine Kinase (MERTK), a transmembrane tyrosine kinase receptor, was significantly up-regulated in smokers. MERTK expression was then assessed in AM of smokers vs nonsmokers by TaqMan RT-PCR, immunohistochemistry, Western and flow analysis. Smoker AM had up-regulation of MERTK mRNA levels (smoker vs non-smoker, 3.6-fold by microarray, p<0.003; 9.5-fold by TaqMan RT-PCR, p<0.02). Immunohistochemistry demonstrated a qualitative increase in MERTK protein expression on AM of smokers. Increased protein expression of MERTK on AM of smokers was confirmed by Western and flow analyses (p< 0.007 and p< 0.0002, respectively). MERTK, a cell surface receptor that recognizes apoptotic cells, is expressed on human AM, and its expression is up-regulated in AM of cigarette smokers. This may reflect an increased demand for removal of apoptotic cells in smokers, an observation with implications for the development of chronic obstructive pulmonary disease (COPD), a disorder associated with dysregulated apoptosis of lung parenchymal cells.
GSE9077 ImmunoHuman PulmonaryFibrosis 10 0 Activation of telomerase often endows cancer cells, but rarely normal somatic cells, with immortality. Especially, fetal lung fibroblasts are known to be hardly immortalized by TERT overexpression. We here established an immortal non-transformed lung fibroblast cell line only by TERT transfection, as well as an immortal transformed cell line by transfection of TERT and SV40 early antigens. Comparing the expression profiles of these cell lines with those of mortal cell strains with elongated lifespan after TERT transfection, 51 genes, including 19 upregulated and 32 downregulated, were explored to be the candidates responsible for regulation of cellular proliferation of lung fibroblasts. These included the genes previously reported to be involved in cellular proliferation, transformation, or self-renewal capacity, and those highly expressed in lung tissues obtained from patients with idiopathic pulmonary fibrosis or hypersensitivity pneumonitis. This set of lung fibrobrast cell lines/strains of identical genetic background with different proliferative capacity, mortal and immortal non-transformed fibroblasts may become useful model cells for research on lung fibroblast growth regulation and the candidate genes explored in this study may provide promising biomarkers or molecular targets of pulmonary fibrosis.
GSE9120 ImmunoHuman Psoriasis 8 1 Interleukin-1 is a proinflammatory and immunomodulatory cytokine that plays a crucial role in inflammatory diseases of the skin, including bacterial infections, bullous diseases, UV damage and especially psoriasis. To characterize the molecular effects of IL-1 in epidermis, we defined the transcriptional changes in human epidermal keratinocytes 1, 4, 24, and 48 h after treatment with IL-1a. IL-1 significantly regulated 388 genes, including genes associated with proteolysis, adhesion, signal transduction, proliferation, and epidermal differentiation. IL-1 induces many genes that have antimicrobial function. Secreted cytokines, chemokines, growth factors, and their receptors are the prominent targets of IL-1 regulation, including IL-8, IL-19, elafin, C3, and S100A proteins, which implicates IL-1 in the pathogenesis of inflammatory diseases. IL-1 induced not only proliferation-associated genes but also differentiation marker genes such as transglutaminase-1 and involucrin, which suggests that IL-1 plays an important role in the aberrant proliferation and differentiation seen in psoriasis. Correlation of IL-1 regulated genes with the TNFa and IFNg regulated ones showed more similarities between IL-1 and TNFa than IL-1 and IFNg, whereas Oncostatin-M affected a largely unrelated set of genes. IL-1 regulates many genes previously shown to be specifically over-expressed in psoriasis. In summary, IL-1 regulates a characteristic set of genes that define its specific contribution to inflammation and aberrant differentiation in skin diseases.
GSE9397 ImmunoHuman ALS 20 1 Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder linked to contractions of the D4Z4 repeat array in the subtelomeric region of chromosome 4q. By comparing genome-wide gene expression data from muscle biopsies of patients with FSHD to those of 11 other neuromuscular disorders, we intend to identify disease-specific changes which are more likely to be involved in the early stages of the disease progression. The data will help to identify pathological mechanisms involved in FSHD.
GSE9452 ImmunoHuman IBD 26 2 The samples are a part of a study aiming at diagnosing ulcerative colitis from genome-wide gene expression analysis of the colonic mucosa. Colonic mucosal samples were collected as endoscopic pinch biopsies from ulcerative colitis patients and from control subjects. Samples with and without macroscopic signs of inflammation were collected from the patients.
GSE9686 ImmunoHuman IBD 33 3 Activation of inflammatory pathways in human IBD\r\nIL-6:STAT3 pathways are activated in the affected colon in IBD. However, the functional implications of this are not known. We hypothesized that pro-inflammatory IL-6:STAT3 dependent networks would be up regulated in the colon of pediatric patients with Crohn Disease (CD) and Ulcerative Colitis (UC), and that these would regulate leukocyte survival, proliferation, and recruitment to the gut. These experiments tested differential colon gene expression relative to these pathways in healthy, CD, and UC samples. Colon biopsy samples were obtained from CD and UC patients at diagnosis, CD patients during therapy, and healthy controls. The global pattern of gene expression was determined using GeneSpring software, and biological networks were identified using Ingenuity software. Data suggested that two IL-6:STAT3 dependent networks are up regulated in pediatric IBD both at diagnosis and during therapy which regulate leukocyte recruitment and survival. The degree of up regulation of these genes compared to healthy controls was remarkably conserved across the two CD groups and the UC groups, suggesting common mechanisms of mucosal inflammation.
GSE9770 ImmunoHuman AD 34 5 Layer II stellate neurons (entorhinal cortex) and layer III cortical neurons (hippocampus CA1, middle temporal gyrus, posterior cingulate, superior frontal gyrus, primary visual cortex) were gene expression profiled. Brain regions are from non-demented individuals with intermediate Alzheimer's disease neuropathologies
GSE994 ImmunoHuman COPD 75 2 A number of studies have shown that cigarette smoking produces a field defect, such that genetic mutations induced by smoking occur throughout the lung and its intra and extra-pulmonary airways. Based on this concept, we have begun this study, which has as its goal the definition of the normal airway transcriptome, an analysis of how that transcriptome is affected by cigarette smoke, and to explore the reversibility of altered gene expression when smoking has been discontinued. We have obtained brushings from intra-pulmonary airways (the right upper lobe carina) and scrapings from the buccal mucosa, from normal smoking and non-smoking volunteers (including 34 Current Smokers, 23 Never Smokers and 18 Former Smokers). RNA was isolated from these samples and gene expression profiles from intra-pulmonary airway epithelial cells were analyzed using Affymetrix U133A human gene expression arrays. All microarray data from the experiments described above have been stored, preprocessed and analyzed in a relational MySQL database that is accessible through our website at http://pulm.bumc.bu.edu/aged
GSE9988 ImmunoHuman Inflammation 62 5 TREM-1 is an orphan immunoreceptor expressed on monocytes, macrophages, and neutrophils. TREM-1 associates with and signals via the adapter protein DAP12/TYROBP, which contains an immunoreceptor tyrosine-based activation motif (ITAM). TREM-1 activation by receptor cross-linking is pro-inflammatory, and can amplify cellular responses to Toll-like receptor (TLR) ligands such as bacterial lipopolysaccharide (LPS). To investigate the cellular consequences of TREM-1 activation, we have characterized global gene expression changes in human monocytes in response to TREM-1 cross-linking in comparison to and combined with LPS. Both TREM-1 activation and LPS up-regulate chemokines, cytokines, matrix metalloproteases, and PTGS/COX2, consistent with a core inflammatory response. However, other immunomodulatory factors are selectively induced, including SPP1 and CSF1 (i.e., M-CSF) by TREM-1 activation and IL-23 and CSF3 (i.e., G-CSF) by LPS. Additionally, cross-talk between TREM-1 activation and LPS occurs on multiple levels. While synergy in GM-CSF protein production is reflected in commensurate mRNA abundance, comparable synergy in IL-1b protein production is not. TREM-1 activation also attenuates the induction of some LPS target genes, including those that encode IL-12 cytokine family subunits. Whereas positive TREM-1 outputs are abolished by the PI3K inhibitor wortmannin, this attenuation is largely PI3K-independent. These experiments provide a detailed analysis of the cellular consequences of TREM-1 activation, and highlight some of the complexity in signal integration between ITAM- and TLR-mediated signaling.
GSE1009 CVMHuman BI-requested 6 1 Gene expression profiling in glomeruli from human kidneys with diabetic nephropathy
GSE10161 CVMHuman CVD 27 1 Left ventricular mass (LVM) and cardiac gene expression are complex traits regulated by factors both intrinsic and extrinsic to the heart. To dissect the major determinants of LVM, we combined expression quantitative trait locus1 and quantitative trait transcript (QTT) analyses of the cardiac transcriptome in the rat. Using these methods and in vitro functional assays, we identified osteoglycin (Ogn) as a major candidate regulator of rat LVM, with increased Ogn protein expression associated with elevated LVM. We also applied genome-wide QTT analysis to the human heart and observed that, out of 22,000 transcripts, OGN transcript abundance had the highest correlation with LVM. We further confirmed a role for Ogn in the in vivo regulation of LVM in Ogn knockout mice. Taken together, these data implicate Ogn as a key regulator of LVM in rats, mice and humans, and suggest that Ogn modifies the hypertrophic response to extrinsic factors such as hypertension and aortic stenosis.
GSE10334 CVMHuman CVD 247 1 We examined gene expression signatures in healthy and diseased gingival tissues in 90 patients. Analysis of the gingival tissue transcriptome in states of periodontal health and disease may reveal novel insights of the pathobiology of periodontitis.
GSE10946 CVMHuman Obesity 23 3 Objective: The etiology of PCOS is mostly unknown. Existing data support both genetic and environmental factors in its pathogenesis. Design: Prospective case - control study. Setting: University Hospital. Patients: 25 patients undergoing IVF-ICSI treatment. Intervention: Genome-wide oligonucleotide microarray technology was used to study differential gene-expression patterns of cultured human cumulus cells from IVF patients divided into 4 groups according to disease state (PCOS vs. Control) and BMI (Obese vs. Lean). Results: Two differential PCOS gene expression profiles were established: Lean-Type was formed by comparing PCOS lean (PL) vs. non-PCOS lean (NL) individuals; Obese-Type was formed by comparing PCOS obese (PO) vs. non-PCOS (NO) obese patients. Conclusions: Different molecular pathways are associated with PCOS in Lean and Obese individuals, as demonstrated by gene expression profiling of cumulus cells. Our findings provide insights into the molecular pathogenesis of PCOS.\r\nWe used microarrays to study the gene expression of human cultured cumulus cells. We compared the genes expression of lean PCOS, Obese PCOS, lean controls and obese controls. Different molecular pathways are associated with PCOS in Lean and Obese patients.
GSE11227 CVMHuman CKD 16 1 Nocturnal home hemodialysis (NHD) [5 – 6 times a week, 6-8 hours per session] augments uremia clearance and is associated with an increase in hemoglobin level. We have used microarray to have a global image of the changes at the gene expression.
GSE1145 CVMHuman CVD 107 8 To establish changes in cardiac transcription profiles brought about by heart failure we collected myocardial samples from patients undergoing cardiac transplantation whose failure arises from different etiologies (e.g. idiopathic dilated cardiomyopathy, ischemic cardiomyopathy, alcoholic cardiomyopathy, valvular cardiomyopathy, and hypertrophic cardiomyopathy) and from "normal" organ donors whose hearts cannot be used for transplants. The transcriptional profile of the mRNA in these samples will be measured with gene array technology. Changes in transcriptional profiles can be correlated with the physiologic profile of heart-failure hearts acquired at the time of transplantation.
GSE11524 CVMHuman CVD 30 1 In sickle cell disease, ischemia-reperfusion injury and intravascular hemolysis produce endothelial dysfunction and vasculopathy characterized by reduced nitric oxide (NO) and arginine bioavailability. Recent functional studies of platelets in patients with sickle cell disease reveal a basally activated state, suggesting that pathological platelet activation may contribute to sickle cell disease vasculopathy. Studies were therefore undertaken to examine transcriptional signaling pathways in platelets that may be dysregulated in sickle cell disease. We demonstrate and validate here the feasibility of comparative platelet transcriptome studies on clinical samples from single donors, by the application of RNA amplification followed by microarray-based analysis of 54,000 probe sets. Data mining an existing microarray database, we identified 220 highly abundant genes in platelets and a subset of 72 relatively platelet-specific genes, defined by more than 10-fold increased expression compared to the median of other cell types in the database with amplified transcripts. The highly abundant platelet transcripts found in the current study included 82% or 70% of platelet abundant genes identified in two previous gene expression studies on non-amplified mRNA from pooled or apheresis samples, respectively. On comparing the platelet gene expression profiles in 18 patients with sickle cell disease in steady state to 12 African American controls, at a 3-fold cut-off and 5% false discovery rate, we identified ~100 differentially expressed genes, including multiple genes involved in arginine metabolism and redox homeostasis. Further characterization of these pathways using real time PCR and biochemical assays revealed increased arginase II expression and activity and decreased platelet polyamine levels. These studies suggest a potential pathogenic role for platelet arginase and altered arginine and polyamine metabolism in sickle cell disease and provide a novel framework for the study of disease-specific platelet biology.
GSE11917 CVMHuman CVD 105 15 Chondro/osteoblastic and cardiovascular-disease associated genes are modulated in human coronary artery smooth muscle cells that calcify in the presence of phosphate and vitamin D sterols.\r\nLooking at the effect of media conditions with and without Vitamin D, paracalcitriol (a vitamin D analog), or R568 (a calcimimetic) vs. dose and time on calcification of human coronary smooth muscle cells.
GSE121 CVMHuman Diabetes 10 1 Global transcript profiling to identify differentially expressed skeletal muscle genes in insulin resistance, a major risk factor for Type II (non-insulin-dependent) diabetes mellitus. Compared gene expression profiles of skeletal muscle tissues from 18 insulin-sensitive versus 17 insulin-resistant equally obese, non-diabetic Pima Indians.
GSE12288 CVMHuman CVD 222 1 Gene expression profile in circulating leukocytes identifies patients with coronary artery disease\r\nPeter Sinnaeve, Mark Donahue, Peter Grass, Jacky Vonderscher, David Seo, Pascal Goldschmidt, Christopher Granger\r\nDepartment of Medicine, Duke University, Durham, NC, USA, Novartis Institute for Biomedical Research, Cambridge, Boston, MA, USA\r\nIntroduction\r\nSystemic and local inflammation plays a prominent pathogenetic role in atherosclerotic coronary artery disease (CAD), but the relationship of phenotypic changes in circulating leukocytes and extent of CAD remains unclear. We have investigated whether gene expression patterns in circulating leukocytes are associated with presence and extent of CAD.\r\nMethods\r\nPatients undergoing coronary angiography were selected according to their Duke CAD index (CADi), a validated angiographical measure of the extent of coronary atherosclerosis that correlates with outcome. RNA was extracted from 110 patients with CAD (CADi>23) and from 112 partially matched controls without CAD (CADi=0). Gene expression was assessed using Affymetrix U133A chips. Genes correlating with CAD were identified using Spearman’s rank correlation, and predictive gene expression patterns were identified using a partial least squares (PLS) regression analysis.\r\nResults\r\n160 individual genes were found to significantly correlate with CADi (rho>0.2, P<0.0027), although changes in individual gene expression were relatively small (1.2 to 1.5 fold). Using these 160 genes, the PLS multivariate regression resulted in a highly predictive model (r2=0.764, P<0.001). Cross-validation showed that most of the predictive model was carried by only 8 genes (r2=0.752) (table 1).\r\nConclusion\r\nSimultaneous expression pattern of 8 genes appears to be highly predictive for CAD. Peripheral leukocyte gene expression pattern could be a novel non-invasive biomarker for CAD and lead to new pathophysiologic insights.
GSE12408 CVMHuman CVD 39 3 The Cohesin apparatus has a canonical role in sister chromatid cohesion. Heterozygous mutations in Nipped B-like (NIPBL), SMC1A, and SMC3 have been found in 60% of probands with Cornelia de Lange Syndrome (CdLS), a dominant multi-system genetic disorder with variable expression. We have performed a genome-wide transcription assessment as well as cohesin binding analysis using human lymphoblastoid cell lines (LCLs) from probands with CdLS and controls. Here, we report a unique profile of genes dysregulated in CdLS that correlates with different clinical presentations. Genome-wide analysis of cohesin binding demonstrates a preference for intergenic regions suggesting a cis-regulatory function mimicking that of an insulator. However, the binding sites are enriched within the promoter regions of the dysregulated genes and are significantly decreased in CdLS probands, indicating an alternative role of cohesin as a classic transcription factor. Cohesin also co-localizes with CTCF at the boundary elements affecting neighboring gene expression in CdLS probands. We propose that the CdLS phenotype is the result of dysregulated gene expression rather than defective sister chromatid cohesion. Phenotype specific expression profiles are also described.
GSE12643 CVMHuman Diabetes 20 1 Microarray-based studies of skeletal muscle from patients with type 2 diabetes and high-risk individuals have demonstrated that insulin resistance and reduced mitochondrial biogenesis co-exist early in the pathogenesis of type 2 diabetes independent of hyperglycaemia and obesity. It is unknown whether reduced mitochondrial biogenesis or other transcriptional alterations co-exist with impaired insulin-responsiveness in primary human muscle cells from patients with type 2 diabetes.\r\nResults: No single gene was differently expressed after correction for multiple testing, and no biological pathway was differently expressed using both approaches for global pathway analysis. In particular, we found no evidence for differential expression of genes involved in mitochondrial oxidative metabolism. Consistently, there was no difference in mRNA levels of genes known to mediate the transcriptional control of mitochondrial biogenesis, PPARGC1A and NRF-1, or in mitochondrial mass between diabetic and control myotubes.
GSE13015 CVMHuman Diabetes 106 6 Melioidosis is a severe infectious disease caused by Burkholderia pseudomallei, a gram-negative bacillus classified by the NIAID as a category B priority agent. Septicemia is the most common presentation of the disease with 40% mortality rate even with appropriate treatments. Faster diagnostic procedures are required to improve therapeutic response and survival rates. We have used microarray technology to generate genome-wide transcriptional profiles (>48,000 transcripts) of whole blood obtained from patients with septicemic melioidosis (n=32), patients with sepsis caused by other pathogens (n=31), and uninfected controls (n=29). Unsupervised analyses demonstrated the existence of a whole blood transcriptional signature distinguishing patients with sepsis from control subjects. The majority of changes observed were common to both septicemic melioidosis and sepsis caused by other infections, including genes related to inflammation, interferon-related genes, neutrophils, cytotoxic cells, and T cells. Finally, class prediction analysis identified a 37 transcript candidate diagnostic signature that distinguished melioidosis from sepsis caused by other organisms with 100% and 78% accuracy in training and independent test sets, respectively. This finding was confirmed by the independent validation set, which showed 80% prediction accuracy. This signature was highly enriched in genes coding for products involved in the MHC Class II antigen processing and presentation pathway. Transcriptional patterns of whole blood RNA distinguish patients with septicemic melioidosis from patients with sepsis caused by other pathogens. Once confirmed in a large scale trial this diagnostic signature might constitute the basis of a differential diagnostic assay.
GSE13139 CVMHuman CVD 54 16 LOX-1 is the primary endothelial receptor for oxidized LDL in endothelial cells and plays a role in the development of atherosclerosis. Expression profiling was carried out on samples from HAECT cells over-expressing either LOX-1 or GFP control and treated with or without OxLDL over a time course of 2, 6, 12 and 24 Hours. The goal of the study was to identify genes expression changes activated by OxLDL binding to LOX-1 at several different time points.
GSE13290 CVMHuman CVD 57 3 In the present study, we performed transcriptome expression analyses in three independent peripheral blood-derived monocyte subpopulations from patients with chronic coronary occlusions (CTO) and tested for arteriogenesis. Whole-genome mRNA expression analyses were performed on these three monocyte subpopulations, namely: (1) unstimulated-, (2) 3 hours LPS-stimulated-, (3) monocyte-derived macrophages. Whole-genome mRNA expression analysis amongst others confirmed increased expression of IFNbeta-regulated genes in patients with insufficient coronary collateralization (collateral flow index (CFI) =0.37 “nonresponders”), compared with patients having sufficient collateralization (CFI>0.37 “responders”).
GSE14312 CVMHuman Obesity 36 4 A major development in obesity research is the recognition that the condition is characterized by chronic mild inflammation. Within adipose tissue, this involves the infiltration of macrophages as well as a direct inflammatory response of adipocytes. This study has used Agilent whole-genome microarrays to examine the effects of macrophage-conditioned medium on the global inflammatory response of human adipocytes.
GSE14954 CVMHuman Obesity 40 4 We investigated the effect of a saturated (SFA) and a monounsaturated (MUFA) rich diet on insulin sensitivity and adipose tissue gene expression profiles of subjects at risk for metabolic syndrome. A controlled-feeding trial was performed with 20 moderately overweight subjects. Subjects received a SFA-rich or a MUFA-rich diet for 8 weeks. Subcutaneous adipose tissue samples were obtained and insulin sensitivity was measured. Whole genome micro-array analysis was performed on the adipose tissue samples. Consumption of a SFA-rich diet resulted in a pro-inflammatory 'obese-like' gene expression profile while consumption of a MUFA-rich diet caused a more anti-inflammatory profile. This suggests that replacement of dietary SFA by MUFA could prevent adipose tissue inflammation and may reduce the risk for inflammation related diseases such as the metabolic syndrome.
GSE15072 CVMHuman CKD 34 3 Several reports have focused on the identification of biological elements involved in the development of abnormal systemic biochemical alterations in chronic kidney disease, but this abundant literature results most of the time fragmented. To better define the cellular machinery associated to this condition, we employed an innovative high-throughput approach based on a whole transcriptomic analysis and classical biomolecular methodologies. The genomic screening of peripheral blood mononuclear cells revealed that 44 genes were up-regulated in both chronic kidney disease patients in conservative treatment (CKD, n=9) and hemodialysis (HD, n=17) compared to healthy subjects (NORM) (p<0.001, FDR=1%). Functional analysis demonstrated that 11/44 genes were involved in the oxidative phosphorylation system (OXPHOS). Western blotting for COXI and COXIV, key constituents of the complex IV of OXPHOS, performed on an independent testing-group (12 NORM, 10 CKD and 14 HD) confirmed the elevated synthesis of these subunits in CKD/HD patients. However, complex IV activity was significantly reduced in CKD/HD patients compared to NORM (p<0.01). Finally, CKD/HD patients presented higher reactive oxygen species and 8-hydroxydeoxyguanosine levels compared to NORM. Taken together these results suggest, for the first time, that CKD/HD patients may have an impaired mitochondrial respiratory system and this condition may be both the consequence and the cause of an enhanced oxidative stress.
GSE15180 CVMHuman nomodel 60 0 Research shows that children who are reared in households with low socioeconomic status are more vulnerable to heart disease, respiratory infection, and some cancers when they reach adulthood. This study conducted transcriptional profiling of PBMC in healthy adults who were low vs. high in early-life SES to explore the long-lasting genomic effects of early experience.
GSE15653 CVMHuman Diabetes 18 4 Hepatic lipid accumulation is an important complication of obesity linked to risk for type 2 diabetes. To identify novel transcriptional changes in human liver which could contribute to hepatic lipid accumulation and associated insulin resistance and type 2 diabetes (DM2), we evaluated gene expression and gene set enrichment in surgical liver biopsies from 13 obese (9 with DM2) and 5 control subjects, obtained in the fasting state at the time of elective abdominal surgery for obesity or cholecystectomy. RNA was isolated for cRNA preparation and hybridized to Affymetrix U133A microarrays.
GSE15773 CVMHuman Obesity 19 2 Obesity is a risk factor for numerous metabolic disorders; however, not all obese individuals are prone to insulin resistance. The central aim of this study was to identify molecular pathways directly related to insulin resistance independent of BMI in obesity.\r\nWe sought to determine the gene expression signature of adipose tissue in a body mass index (BMI)-matched obese cohort of patients that are either insulin sensitive or insulin resistant.
GSE1657 CVMHuman Obesity 42 6 Fat tissue was resected during gastric bypass surgery for management of obesity. All subjects had fasted at least 10 hours before surgery. Subjects with malignancies were excluded. No subjects were taking thiazolidinediones or steroids. None had fasting plasma glucose levels over 120 mg/ dl. One half to 10 g of abdominal subcutaneous (external to the fascia superficialis), mesenteric, and greater omental fat were obtained from each subject. The tissue was collected in Hank’s balanced salt solution with bicarbonate, penicillin, and gentamicin. Fat tissue was minced and then digested in HBSS containing 1 mg/ml collagenase and 7.5% fetal bovine serum in a 37*C shaking water bath until fragments were no longer visible and the digest had a milky appearance. Digests were filtered and centrifuged at 800xG for 10 min. The digests were treated with an erythrocyte lysis buffer. Cells were plated in 1:1 Dulbecco’s modified Eagle’s medium:Ham’s F12 that contained 10% fetal bovine serum and antibiotics at a density of 4 x 104 cells/cm2. After 18 hours cultures were trypsinized until 95% of cells were detached (leaving endothelial cells and macrophages behind) and re-plated. Macrophages were rare (less than 5 per 106 cells, as assessed by phase contrast microscopy) in the re-plated cultures, irrespective of fat depot origin. Plating medium was changed every 2 days until confluence. For differentiation, preadipocytes were treated for 30 days with plating medium (without serum) enriched with 100 nM dexamethasone, 500 nM human insulin, 200 pM triiodothyronine, 0.5 *M rosiglitazone, antibiotics, and 540 *M methylisobutylxanthine (removed after 2 days). Higher rosiglitazone and insulin concentrations did not further enhance differentiation. Medium was changed every 2 days. For the final 2 days, differentiation medium was removed and cells were cultured in plating medium without serum. Undifferentiated preadipocytes were maintained in plating medium until confluence, when serum was removed for 2 days. For telomerase-expressing clones, preadipocytes were isolated and when cells had undergone 7 population doublings, they were transduced with a retrovirus containing the plasmid, pBABE-hTERT-Hygro. This vector expresses the human telomerase reverse transcriptase component (hTERT) driven by the Moloney murine leukemia virus long terminal repeat promoter and a hygromycin resistance sequence driven by the SV40 promoter. The 3 abdominal subcutaneous and 3 omental stably transduced, hygromycin-resistant clones capable of achieving confluence fastest were selected from 38 subcutaneous and 42 omental clones. Telomerase activity in these clones was verified using a PCR-based telomere repeat amplification protocol. RNA was isolated from preadipocytes by the Trizol method. RNA samples were labeled using the standard one-cycle Affymetrix GeneChip Eukaryotic Target Labeling Assay for Expression Analysis. Samples were hybridized for 16 hours at 45 ºC and 60 rpm, washed and stained according to the standard Affymetrix Antibody Amplification for Eukaryotic Targets protocol, and scanned at 488 nm. Images were quantified and linearly scaled using Affymetrix GeneChip Operating Software 1.1 using default analysis settings.
GSE16797 CVMHuman CVD 34 5 Clinical score and transcript abundance patterns identify Kawasaki disease patients who may benefit from addition of methylprednisolone.\r\nIntravenous immunoglobulin (IVIG) treatment-resistant patients are high risk of developing coronary artery lesions (CALs) with Kawasaki disease (KD). The IVIG-responsive (Group A; n = 6) and -resistant patients (Group B) were predicted before starting the initial treatment using the Egami scoring system, and randomly allocated a single-IVIG treatment group (Group B1; n = 6) or a IVIG-plus-methylprednisolone (IVMP) combined therapy group (Group B2; n = 5). We investigated transcript abundance in the leukocytes of those patients using microarray analysis.\r\nResults: five patients in Group A and 1 patient in Group B1 responded to initial IVIG treatment. All Group B2 patients responded to IVIP-plus-IVMP combined therapy. Prior to performing these treatments, those transcripts related to IVIG-resistance and to the development of CALs, such as IL1R, IL18R, oncostatin M, suppressor of cytokine signaling-3, S100A12 protein, carcinoembryonic antigen-related cell adhesion molecule-1, matrix metallopeptidase-9 and polycythemia rubra vera-1 were more abundant in Group B patients in comparison to Group A patients. Moreover, those transcripts in Group B2 patients were more profoundly and broadly suppressed than Group B1 patients after treatment. Conclusion: this study elucidated the molecular mechanism of the effectiveness of IVIG-plus-IVMP combined therapy.
GSE17078 CVMHuman CVD 30 1 Protein C (PC) deficiency increases the risk of venous thrombosis (VT) among members of Kindred Vermont II, but fails to fully account for the inheritance pattern. A genome scan of the pedigree supported the presence of a prothrombotic gene on chromosome 11q23 with weaker support on chromosomes 10p12 and 18p11.2-q11.\r\nPreliminary data from Affimetrix microarray expression analysis of Blood Outgrowth Endothelial Cells of 3 members of Kindred Vermont II compared to a well established normal control group indicated that IgsF4 was decreased in patients versus controls. In addition, both statistical and pathway analysis results suggested that these genes are associated protein C. Further studies indicated that Cell Adhesion Molecule 1 (CADM1), a member of the IgsF4 superfamily, may be associated with VT.
GSE17114 CVMHuman CVD 29 1 Behçet’s disease (BD) is a multisystemic immuno-inflammatory disorder characterized by a generalized vasculitis, particularly at the orogenital mucosa and eye. It is a complex disease with unclear pathogenesis.\r\nTo better understand BD´s etiology, we performed genomic expression profiling of patients and controls.
GSE1719 CVMHuman CVD 36 1 Age-related macular degeneration has a strong epidemiological association with cardiovascular disease. One pathogenic hypothesis that applies to both diseases is the concept of an abnormal cellular response to injury resulting in a disease phenotype. It has been hypothesized that this phenotype is also present in dermal fibroblasts. This study tests this hypothesis by examination of the expression profiles of fibroblasts obtained from diseased patients and subjected to sublethal cell injury.
GSE17371 CVMHuman Obesity 12 1 Skeletal muscle (rectus femoris) gene expression was analyzed from diet-resistant and diet-sensitive obese women undergoing clinically supervised weight-loss at a weight management clinic\r\nThe goal of the study was to characterize global gene expression profiles in skeletal muscle from obese women, prior to their participation in a clinically supervised, low-calorie diet, weight management program. Following entry into the weight-loss program, subjects can be categorized as being 'diet-sensitive' or 'diet-resistant' depending on the rates of weight loss achieved. In the current study, we selected an equal number of diet-sensitive and diet-resistant subjects for comparative expression profiling
GSE17582 CVMHuman CVD 48 5 Patients with combined heart and renal failure, also termed the cardiorenal syndrome (CRS), have high cardiovascular morbidity and mortality. Several key connectors between heart and kidney have been recognized, such as oxidative stress, inflammation, the renin-angiotensin system and the sympathetic nervous system. Monocytes are key players in the development of atherosclerosis and may act as a biosensor to detect changes in the systemic environment. Anemia, which occurs frequently in CRS, is partly due to an absolute and/or relative erythropoietin (EPO) deficiency. Until now, EPO treatment has largely been used to treat (renal) anemia, but recent research also showed beneficial non-hematopoietic effects such as anti-inflammatory and anti-oxidative capacities. The hypothesis of the present study was that monocyte gene expression profiles of cardiorenal patients compared to healthy controls reflect the systemic nature of CRS and are responsive to short-term treatment with Epo. The first aim was to investigate whether this short term treatment revealed non-hematopoietic EPO effects. The second aim was to address whether EPO dampens expression of genes involved in inflammation and oxidative stress. Given the variable response to EPO, the third aim was to test whether baseline gene expression profiles or the acute gene expression modulation by EPO are associated with EPO resistance.
GSE17800 CVMHuman CVD 48 1 Background: Immunoadsorption with subsequent IgG substitution (IA/IgG) represents a novel therapeutic approach in treatment of dilated cardiomyopathy (DCM) which leads to improvement of left ventricular ejection fraction (LVEF). However, response to this therapeutic intervention shows wide inter-individual variability. In this pilot study, we tested the value of clinical, biochemical and molecular parameters for prediction of the response of patients with DCM to IA/IgG.\r\nMethods & Results: Forty DCM patients underwent endomyocardial biopsies (EMBs) before IA/IgG. In 8 patients with normal LVEF (controls) EMB were obtained for clinical reasons. Clinical parameters, negative inotropic activity (NIA) of antibodies on isolated rat cardiomyocytes and gene expression profiles of EMBs were analyzed. DCM patients displaying improvement of LVEF (= 20% relative and = 5% absolute) six month after IA/IgG were considered responders. Compared to non-responders (n=16), responders (n=24) displayed shorter disease duration (p=0.006), smaller LV internal diameter in diastole (LVIDd) (p=0.019) and stronger NIA of antibodies. Antibodies obtained from controls were devoid of NIA. Myocardial gene expression patterns were different in responders and non-responders for genes of oxidative phosphorylation, mitochondrial dysfunction, hypertrophy, and ubiquitin proteasome pathway. Integration of scores of NIA and expression levels of four genes allowed robust discrimination of responders from non-responders at baseline (sensitivity of 100 % (95% CI, 85.8%-100%); specificity up to 100% (95 % CI, 79.4%-100%, cut-off value: -0.28), and was superior to scores derived from antibodies, gene expression or clinical parameters only.\r\nConclusion: Combined assessment of NIA of antibodies and gene expression patterns of DCM patients at baseline predicts response to IA/IgG therapy and may enable appropriate selection of patients who benefit from this therapeutic intervention.
GSE18084 CVMHuman CVD 39 1 Analysis of IgM+CD27+ B cells in individuals with hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC). We have previously shown that HCV+MC+ individuals have clonal expansions of IgM+ memory B cells. This study aims to characterize differentially expressed genes in peripheral IgM+CD27+ B cells in HCV RNA+MC+ individuals, compared to HCV RNA+MC- subjects and HCV RNA- healthy controls. IgM+ B cells were isolated form donor PBMCs by immunomagnetic negative selection, and the CD27+ subset was further purified by positive selection. 2ng RNA was isolated from cells and amplified using the Nugen WT-Ovation Amplification Kit. cDNA was synthesized, biotin labeled, and hybridized to Illumina human v2 microarrays. Data were collected and analyzed with Illumina Genome Studio. Raw data were normalized by transforming measurements less than 0.01 to 0.01, normalizing per chip to the 50th percentile, and normalizing per gene to the median. Normalized data were then filtered to remove genes with control signals <170. Genes that were significantly upregulated in HCV RNA+MC+ vs HCV RNA+MC- subjects' IgM+CD27+ B cells were identified using a Welch t-test with p-calue cutoff 0.05 and Benjamini-Hochberg false discovery rate of 0.05. The resulting gene list was then filtered for genes showing >2-fold differential expression.
GSE1869 CVMHuman CVD 37 5 Pre-LVAD and explanted ischemic and nonischemic cardiomyopathy and nonfailing hearts all normalized with RMA
GSE18732 CVMHuman Diabetes 118 2 We used microarray technology to profile mRNA expression in the skeletal muscle of normal (NGT), glucose intolerant (IGT) and type 2 diabetic (DM) subjects. Groups were classified using WHO criteria and, importantly, the DM group were free of anti hypoglycaemic medication for one week prior to biopsy.
GSE18897 CVMHuman Obesity 80 4 We have carried out whole-genome expression profiling of whole blood from obese subjects, defined as obese diet-sensitive and obese diet-resistant, and well matched lean individuals. The diet-sensitive or diet-resistant status refers to the different rates of weight loss observed in the two groups on a low-calorie diet regimen. Bioinformatic analysis revealed alterations in transcription in key pathways that are consistent with impaired capacity for fatty acid oxidation driven mitochondrial ATP synthesis in obese subjects who are resistant to weight loss.
GSE19151 CVMHuman CVD 133 1 Venous thromboembolism (VTE) is a major cause of morbidity and mortality. Pulmonary embolism is a life threatening manifestation of VTE that occurs in at least half the patients on presentation. In addition, VTE recurs in up to 30% of patients after a standard course of anticoagulation, and there is not a reliable way of predicting recurrence. We investigated whether gene expression profiles of whole blood could distinguish patients with VTE from healthy controls, single VTE from those with recurrence, and DVT alone from those with PE. 70 adults with VTE on warfarin and 63 healthy controls were studied. Patients with antiphospholipid syndrome or cancer were excluded. Blood was collected in PAXgene tubes, RNA isolated, and gene expression profiles obtained using Affymetrix arrays. We developed a 50 gene model that distinguished healthy controls from subjects with VTE with excellent receiver operating characteristics (AUC 0.94; P < 0.0001). We also discovered a separate 50 gene model that distinguished subjects with a single VTE from those with recurrent VTE with good receiver operating characteristics (AUC 0.75; P=0.008). In contrast, we were unable to distinguish subjects with DVT from those with PE using gene expression profiles. Gene expression profiles of whole blood can distinguish subjects with VTE from healthy controls and subjects with a single VTE from those with recurrence. Additional studies should be performed to validate these results and develop diagnostic tests. Gene expression profiling is likely translatable to other thrombotic disorders(e.g., patients with cancer and VTE).
GSE19790 CVMHuman Diabetes 22 1 To investigate the effects of bariatric surgery on gene expression profile changes in whole blood in obese subjects with type 2 diabetes in a pilot study setting. Whole blood from eleven obese subjects with type 2 diabetes was collected in PAXgene tubes prior to and 6-12 months after bariatric surgery. Total RNA was isolated, amplified, labeled and hybridized to Illumina gene expression microarrays. Clinical and expression data were analyzed using a paired t-test, and correlations between changes in clinical trait and transcript levels were calculated. Pathways were identified using Ingenuity Pathway Analysis and DAVID gene ontology software. Bariatric surgery resulted in significant reduction of BMI, fasting plasma glucose and normalization of HbA1c levels. The expression levels of 204 transcripts, representing 200 unique genes, were significantly altered after bariatric surgery. Among the significantly regulated genes were GGT1, CAMP, DEFA1, LCN2, TP53, ZNF684, GPR50, PDSS1, OLR1, CNTNAP5, DHCR24, HHAT and SARDH, which have been previously implicated in lipid metabolism, obesity and/or type 2 diabetes. The changes in expression of seven transcripts, WDR35, FLF45244, DHCR24, TIGD7, TOPBP1, TSHZ1, and FAM8A1 were strongly correlated with the changes in body weight, fasting plasma glucose and HbA1c content.\r\nThese preliminary data suggest that whole blood expression levels of specific transcripts may identify biomarkers associated with susceptibility for type 2 diabetes and/or therapeutic response.
GSE20129 CVMHuman CVD 135 5 This study is to compare the mRNA expression differences between atherosclerosis and non-atherosclerosis samples from female peripheral blood. The possible effects of races are also considered.
GSE20247 CVMHuman BI-requested 18 3 Microarray analysis reveals up-regulation of retinoic acid and hepatocyte growth factor related signaling pathways by pro-insulin C-peptide in kidney proximal tubular cells: Antagonism of the pro-fibrotic effects of TGF-b1\r\nNovel signaling roles for C-peptide have recently been discovered with evidence that it can ameliorate complications of type 1 diabetes. Here we sought to identify new pathways regulated by C-peptide of relevance to the pathophysiology of diabetic nephropathy. Microarray analysis was performed to identify genes regulated by either C-peptide and/or transforming growth factor beta 1 (TGF-ß1) in a human proximal tubular cell line, HK-2. Expression of retinoic acid receptor ß (RARß), hepatcoyte growth factor (HGF), cellular retinoic acid binding protein II (CRABPII), vimentin, E-cadherin, Snail and ß-catenin was assessed by immunoblotting. The cellular localisation of vimentin and ß-catenin was determined by immunocytochemistry. Changes in cell morphology were assessed by phase contrast microscopy. Gene expression profiling demonstrated differential expression of 953 and 1,458 genes after C-peptide exposure for 18h or 48h respectively. From these, members of the anti-fibrotic retinoic acid (RA) and HGF signaling pathways were selected. Immunoblotting demonstrated that C-peptide increased RARß, CRABPII and HGF. We confirmed a role for RA in reversal of TGF-ß1-induced changes associated with epithelial-mesenchymal transition (EMT), including expression changes in Snail, E-cadherin, vimetin and redistribution of ß-catenin. Importantly, these TGF-ß1-induced changes were inhibited by C-peptide. Further, effects of TGF-ß1 on Snail and E-cadherin expression were blocked by HGF and inhibitory effects of C-peptide were removed by blockade of HGF activity. This study identifies a novel role for HGF as an effector of C-peptide, possibly via an RA signaling pathway, highlighting C-peptide as a potential therapy for diabetic nephropathy.
GSE20680 CVMHuman CVD 195 2 Expression profiling of whole blood cells isolated from patients piror to undergoing cardiac catheterization.\r\nThe Cathgen Registry is a single-center coronary catheter-lab cohort being run at Duke University for the purpose of identifying biomarkers associated with coronary disease.
GSE20681 CVMHuman CVD 198 1 Expression profiling of whole blood cells isolated from patients piror to undergoing cardiac catheterization.\r\nPREDICT is a prospective, multi-center coronary catheter-lab trial being run in the US for the purpose of identifying biomarkers associated with coronary disease. A summary of the trial can be found at http://clinicaltrials.gov (identifier # NCT00500617).
GSE20931 CVMHuman Obesity 24 1 The hypothesis tested in the present study was The effect fo weight loss by dietary intervention with very low calorie diet on colorectal inflammatory genes and genepathways. The study results have shown that a 10% weight loss in obese women down-regulated inflammatory and cancer gene pathways. In addition there was downregulation of transcription factors known to play an important role in colorectal cancer.
GSE20950 CVMHuman Obesity 39 2 Obesity is a risk factor for numerous metabolic disorders; however, not all obese individuals are prone to insulin resistance. The central aim of this study was to identify molecular pathways directly related to insulin resistance independent of BMI in obesity.\r\nWe sought to determine the gene expression signature of adipose tissue in a body mass index (BMI)-matched obese cohort of patients that are either insulin sensitive or insulin resistant.
GSE20966 CVMHuman Diabetes 20 1 Changes in gene expression in pancreatic beta-cells from type 2 diabetes could provide insights into their abnormal insulin secretion and beta-cell turnover. The laser capture microdissection technique was used to acquire beta-cells from pancreatic tissue sections obtained from type 2 diabetic (T2D) and non-diabetic controls. We found that 4% of analyzed transcripts were differentially expressed between the two groups at the lower confidence bound cutoff of 1.2, and, among the differentially expressed transcripts, 62% were up-regulated and 38% down-regulated in samples of T2D subjects compared to non-diabetic controls. We observed: 1) changes in expression of genes linked to glucotoxicity, in particular, up-regulation of LDHA and PCK1, and down-regulation of GPD2, ME1 and ACLY; 2) evidence of oxidative stress, documented by up-regulation of metallothionein genes; 3) few changes in the major genes associated with cell cycle, apoptosis or endoplasmic reticulum stress; 4) differential expression of genes associated with pancreatic regeneration, most notably up-regulation of members of the regenerating islet gene (REG) family and metalloproteinase 7; and 5) differential expression of some genes found in genome wide association studies to be related to T2D (IGF2BP2, TSPAN8, and HNF1B were up-regulated, while JAZF1 and SLC30A8 were down-regulated). In conclusion, this study has identified many novel changes in pancreatic beta-cell gene expression that enhance the understanding of the pathogenesis of T2D.
GSE21342 CVMHuman Obesity 56 4 This study contrasts the expression profiles of peripheral blood leukocytes from third trimester pregnant mothers, with cord blood leukocytes from their newborn children. It is a companion to (GSE21311). After normalization for RNA integrity, major principal components of the variation were found to distinguish individuals. Transmission of gene expression profiles from mother to child was documented, along with differences between gestational diabetic, obese, and normal weight mothers and their children.
GSE21610 CVMHuman CVD 68 2 Mechanical unloading by ventricular assist devices (VAD) leads to significant gene-expression changes often summarized as reverse remodeling. However, little is known on individual transcriptome changes during VAD-support and its relationship to non-failing hearts (NF). In addition no data are available for the transcriptome regulation during non-pulsatile VAD-support. Therefore we analysed the gene-expression patterns of 30 paired samples from VAD-supported (including 8 non-pulsatile VADs) and 8 non-failing control hearts (NF) using the first total human genome-array available.\r\nTransmural myocardial samples were collected for RNA-isolation. RNA was isolated by commercial methods and processed according to chip-manufacturer recommendations. cRNA were hybridized on Affymetrix HG-U133 Plus 2.0 arrays, providing coverage of the whole human genome Array. Data was analyzed using Microarray Analysis Suite 5.0 (Affymetrix) and clustered by Expressionist software (Genedata). 352 transcripts were differentially regulated between samples from VAD-implantation and NF, whereas 510 were significantly regulated between VAD-transplantation and NF (paired t-test p<0.001, fold change >=1.6). Remarkably, only a minor fraction of 111 transcripts was regulated in heart failure (HF) and during VAD-support. Unsupervised hierarchical clustering of paired VAD- and NF-samples revealed separation of HF- and NF- samples, however individual differentiation of VAD-implantation and VAD-transplantation was not accomplished. Clustering of pulsatile and non-pulsatile VAD did not lead to robust separation of gene expression patterns.\r\nDuring VAD-support myocardial gene expression changes do not indicate reversal of the HF-phenotype, but reveal a distinct HF-related pattern. Transcriptome analysis of pulsatile and non-pulsatile VAD-supported hearts did not provide evidence for a pump-mode specific transcriptome pattern.
GSE21785 CVMHuman CKD 12 1 Glomerular diseases account for the majority of cases with chronic renal failure. Several genes have been identified with key relevance for glomerular function. Quite a few of these genes show a specific or preferential mRNA expression in the renal glomerulus. To identify additional candidate genes involved in glomerular function in humans we generated a human renal glomerulus-specific transcript dataset (GTD) by comparing gene expression profiles from human glomeruli and tubulointerstitium obtained from six transplant living donors using Affymetrix HG-U133A arrays. This analysis resulted in 677 genes with prominent overrepresentation in the glomerulus. Genes with ‘a prior’i established known prominent glomerular expression served for validation and were all found in the novel expression library (e.g. CDKN1, DAG1, DDN, EHD3, MYH9, NES, NPHS1, NPHS2, PDPN, PLA2R1, PLCE1, PODXL, PTPRO, SYNPO, TCF21, TJP1, WT1). The mRNA expression for several novel glomerulus-enriched genes identified in REGGEL was validated by qRT-PCR. Gene ontology and pathway analysis identified biological processes previously not reported to be of relevance in glomeruli including among others axon guidance. This finding was further validated by assessing the expression of the axon guidance molecules neuritin (NRN1) and roundabout receptor ROBO1 and -2. Glomerular disease associated differential mRNA regulation of ROBO2 was found in diabetic nephropathy.\r\nIn summary, using a comparative strategy on microdissected nephrons novel transcripts with predominant expression in the human glomerulus could be identified. A systematic analysis of this glomerulus-specifc gene expression library allows the detection of target molecules and biological processes involved in glomerular biology and renal disease.
GSE21891 CVMHuman Diabetes 129 2 We carried out a high throughput analysis of insulin-induced kinase signaling pathways in primary fibroblasts from 35 unrelated individuals. We found that extensive individual variation exists in induction of various signaling pathways. ERK signaling displayed the greatest variation, which led to extensive variation in expression of downstream target genes.\r\nOur results suggest that phenotypic variation in kinase signaling mediates variation in downstream processes of insulin response. Future study of such phenotypic variation is important to linking genetic variants to individual susceptibility to complex diseases such as diabetes.
GSE22070 CVMHuman nomodel 142 0 Subcutaneous adipose tissue and visceral adipose tissue samples were obtained from severely obese individuals that underwent bariatric surgery.\r\nThe goal of this study was to compare genome-wide gene expression levels in the two tissue types from healthy and unhealthy severely obese individuals.\r\nWhole-transcriptome subcutaneous adipose tissue gene expression levels were determined in 73 individuals with a BMI >35 kg/m2.\r\nWhole-transcriptome visceral adipose tissue gene expression levels were determined in 69 individuals with a BMI >35 kg/m2.\r\nModules of co-expressed genes likely to be functionally related were identfied and correlated with BMI, plasma levels of glucose, insulin, HbA1c, triglycerides, non-esterified fatty acids, ALAT, ASAT, C-reactive protein, and LDL- and HDL cholesterol.
GSE22253 CVMHuman CVD 108 2 Genome-wide association studies have identified a small region at chromosome 9p21.3 strongly associated with coronary heart disease risk. The region contains no protein-coding genes and the mechanism underlying its association with heart disease is unknown. We investigated associations between rs1333049, a single nucleotide polymorphism representing the 9p21.3 locus, and levels of cardiac gene expression in myocardial tissue from donors with no documented history of heart disease.
GSE22255 CVMHuman CVD 40 1 Stroke is a “brain attack” cutting off vital blood, and consequently the nutrients and oxygen vital to the brain cells that control everything we do. Stroke is a complex disease with unclear pathogenesis resulting from environmental and genetic factors.\r\nTo better understand IS´s etiology, we performed genomic expression profiling of patients and controls.
GSE22309 CVMHuman Diabetes 110 2 Insulin is a potent pleiotropic hormone that affects processes such as cellular growth, differentiation, apoptosis, ion flux, energy expenditure, and carbohydrate, lipid, and protein metabolism.\r\nWe used microarrays to detail the global programme of gene expression underlying the influence of insulin in human skeletal muscle collected from different human individuals including 20 insulin sensitive, 20 insulin resistant and 15 diabetic patients. We identified distinct classes of up-regulated and down-regulated genes during these processes.\r\nThe pathophysiology of obesity represents an imbalance between a high energy intake and/or low energy expenditure. Resting energy expenditure (REE) comprises 60-75% of total energy expenditure. The respiratory quotient (RQ) is used to estimate fuel partitioning between fat and carbohydrate as preferred substrates for energy generation, and fuel preferences to generate REE also exhibit individual variation. Genes influencing REE and RQ could represent candidate genes for obesity, Metabolic Syndrome, and Type 2 Diabetes due to the involvement of these traits in energy balance and substrate oxidation.\r\nWe used microarrays to explore the molecular bases for individual variation in REE and fuel partitioning as reflected by RQ. We performed microarray studies in human vastus lateralis muscle biopsies from 40 healthy subjects with measured REE and RQ values. We identified genes significantly correlated with REE and RQ, respectively.
GSE2240 CVMHuman CVD 70 4 GSE2240 contains two different experimental subsets:\r\n1) Comparison of atrial and ventricular gene expression (atrial tissue of patients with sinus rhythm vs. human left ventricular non-failing myocardium)\r\nThe purpose of our investigation was to identify the transcriptional basis for ultrastructural and functional specialization of human atria and ventricles. Using exploratory microarray analysis (Affymetrix U133A+B), we detected 11,740 transcripts expressed in human heart, representing the most comprehensive report of the human myocardial transcriptome to date. Variation in gene expression between atria and ventricles accounted for the largest differences in this data set, as 3.300 and 2.974 transcripts showed higher expression in atria and ventricles, respectively. Functional classification based on Gene Ontology identified chamber-specific patterns of gene expression and provided molecular insights into the regional specialization of cardiomyocytes, correlating important functional pathways to transcriptional activity: Ventricular myocytes preferentially express genes satisfying contractile and energetic requirements, while atrial myocytes exhibit specific transcriptional activities related to neurohumoral function. In addition, several pro-fibrotic and apoptotic pathways were concentrated in atrial myocardium, substantiating the higher susceptibility of atria to programmed cell death and extracellular matrix remodelling observed in human and experimental animal models of heart failure. Differences in transcriptional profiles of atrial and ventricular myocardium thus provide molecular insights into myocardial cell diversity and distinct region-specific adaptations to physiological and pathophysiological conditions (Barth AS et al., Eur J Physiol, 2005).\r\n2) Comparison of atrial gene expression in patients with permanent atrial fibrillation and sinus rhythm.\r\nAtrial fibrillation is associated with increased expression of ventricular myosin isoforms in atrial myocardium, regarded as part of a dedifferentiation process. Whether re-expression of ventricular isoforms in atrial fibrillation is restricted to transcripts encoding for contractile proteins is unknown. Therefore, this study compares atrial mRNA expression in patients with permanent atrial fibrillation to atrial mRNA expression of patients with sinus rhythm as well as to ventricular gene expression using Affymetrix U133 arrays. In atrial myocardium, we identified 1.434 genes deregulated in atrial fibrillation, the majority of which, including key elements of calcium-dependent signaling pathways, displayed down-regulation. Functional classification based on Gene Ontology provided the specific gene sets of the interdependent processes of structural, contractile and electrophysiological remodeling. In addition, we demonstrate for the first time a prominent up-regulation of transcripts involved in metabolic activities, suggesting an adaptive response to an increased metabolic demand in fibrillating atrial myocardium. Ventricular-predominant genes were five times more likely to be up-regulated in atrial fibrillation (174 genes up-regulated, 35 genes down-regulated), while atrial-specific transcripts were predominantly down-regulated (56 genes up-regulated, 564 genes down-regulated). Overall, in atrial myocardium, functional classes of genes characteristic of ventricular myocardium were found to be up-regulated (e.g. metabolic processes) while functional classes predominantly expressed in atrial myocardium were down-regulated in atrial fibrillation (e.g. signal transduction and cell communication). Therefore, dedifferentiation with adoption of a ventricular-like signature is a general feature of the fibrillating atrium, uncovering the transcriptional response pattern in pmAF (Barth AS et al., Circ Res, 2005).
GSE22435 CVMHuman Obesity 17 1 Alternative mRNA splicing provides transcript diversity and has been proposed to contribute to several human diseases. Here, we demonstrate that expression of genes regulating RNA processing is decreased in both liver and skeletal muscle of obese humans. To determine the metabolic impact of reduced splicing factor expression, we further evaluated the splicing factor, SFRS10, identified as down-regulated in obese human liver and skeletal muscle and in high fat fed rodents. siRNA-mediated reductions in SFRS10 expression induced lipogenesis and lipid accumulation in cultured hepatocytes. Moreover, SFRS10 heterozygous mice have both increased hepatic lipogenic gene expression and hypertriglyceridemia. We also demonstrate that LPIN1, a key regulator of lipid metabolism, is a splicing target of SFRS10, with reduced SFRS10 levels favoring the lipogenic ß isoform of LPIN1. Importantly, LPIN1ß-specific siRNA abolished the lipogenic effects of decreased SFRS10 expression. Together, our results indicate reduced expression of SFRS10 alters LPIN1 splicing and induces lipogenesis, demonstrating that reduced splicing factor expression observed in human tissues may contribute to metabolic phenotypes associated with human obesity.
GSE22688 CVMHuman CVD 38 1 Background: African Americans (AA) have increased burdens of cardiovascular disease and cancer compared to Caucasian Americans (CA). This study addresses the possibility that genetic differences affecting the biology of the vascular endothelium could be a factor contributing to this health disparity.\r\nMethods: From self-identified, healthy, 20-29 year old AA (n=21) and CA (n=17), we established cultures of blood outgrowth endothelial cells (BOEC) and applied microarray profiling. BOEC have never been exposed to in vivo influences, and their gene expression reflects culture conditions (meticulously controlled) and donor genetics. Analysis used two distinct approaches. Significance Analysis of Microarray, a FDR-based test, identified significant differential expression of single genes. Gene Set Enrichment Analysis examined expression of pre-determined gene sets that survey each of nine biological systems relevant to endothelial cell biology.\r\nResults: At the highly stringent threshold of FDR=0, we identified 31 single genes that were differentially expressed, 4 higher and 27 lower in AA. “PSPH” exhibited the greatest fold-change (AA>CA), but this was entirely accounted for by a homolog (PSPHL) hidden within the PSPH probe set. Among other significantly different genes were: for AA>CA, SOS1, AMFR, FGFR3; and for AA<CA, ARVCF, BIN3, EIF4B. Many more (221 transcripts for 204 genes) were differentially expressed at the more customary, less stringent threshold of FDR<.05. Using the biological systems approach, we identified shear response biology as being significantly altered for AA versus CA. It detected an apparent tonic increase of expression (AA>CA) for 46/157 genes within that system.\r\nConclusions: The most significant single gene changes detected for AA involved genes having substantial, known roles in endothelial biology. Biological systems analysis suggested that shear stress response, a critical regulator of endothelial function and vascular homeostasis, may be different between AA and CA. These results potentially have direct implications for the role of endothelial cells in both vascular disease (e.g., hypertension and stroke) and cancer (via angiogenesis). The present findings are consistent with our overarching hypothesis that genetic influences stemming from ancestral continent-of-origin could impact upon endothelial cell biology and thereby contribute to disparity of vascular-related disease burden amongst AA.
GSE23314 CVMHuman BI-requested 403 1 This SuperSeries is composed of the SubSeries listed below.
GSE23338 CVMHuman BI-requested 9 2 TGFbeta is the major cytokine driver of fibrosis in the kidney and other tissue. Epithelial-mesenchymal transition has been postulated to contibrute to renal fibrosis in diseases such as diabetic nephropathy.\r\nWe wished to identify novel genes that were upregulated in human kidney epithelial cells in response to TGFb1.The transcriptional responses for human proximal tubule epithelial cells to 10 ng/ml TGFbeta1 was examined over 24 and 48 hr
GSE23506 CVMHuman Obesity 36 1 Obesity is a major risk factor for several chronic diseases including diabetes, fatty liver disease and cancer. Despite similar propensities for obesity, Hispanics and African Americans exhibit unique and distinct differences in obesity related outcomes such as greater risk of, obesity-related cancers in AA and non alcoholic fatty liver disease (NAFLD) in Hispanics. This study was aimed to determine whether differences in subcutaneous adipose tissue (SAT) gene expression in obese, Hispanic and AA young adults might explain ethnic differences in obesity-related phenotypes.
GSE23746 CVMHuman CVD 95 1 We used microarrays to profile monocytes to identify gene expression differences correlating with disease status in carotid artery atherosclerosis. We identified 1302 genes differentially expressed between control and affected subjects after correcting for clinical covariates. Differential expression was likely caused by unidentified risk factors or systematic manifestations of atherosclerosis itself.
GSE24185 CVMHuman Obesity 103 2 Obesity is thought to contribute to worse disease outcome in breast cancer as a result of increased levels of adipocyte-secreted endocrine factors, insulin, and insulin-like growth factors (IGFs) that accelerate tumor cell proliferation and impair treatment response. We examined the effects of patient obesity on primary breast tumor gene expression, by profiling transcription of a set of tumors for which the patients’ body mass index (BMI) was ascertained. Sample profiles were stratified according to patients’ obesity phenotype defined as normal (BMI <25), overweight (BMI 25-29.9), or obese (BMI>30). Widespread alterations in gene expression were evident in breast tumors from obese patients as compared to tumors from other patients, allowing us to define an obesity-associated cancer transcriptional signature of 662 genes.
GSE24495 CVMHuman nomodel 113 0 In order to identify potential new biomarkers of atherosclerotic plaque composition we performed a large scale analysis of gene expression patterns in human atherosclerotic lesions. Whole genome expression analysis of 101 peripheral plaques identified a robust gene signature (1514 genes) dominated by inflammatory processes, and cholesterol metabolism and storage genes. Specific pathways enriched in this signature included activation of the Toll-like receptor signaling pathway, T-cell activation, cholesterol efflux, oxidative stress response, inflammatory cytokine production, vasoconstriction and lysosomal activity. Analysis of gene expression in plaque micro-dissected material revealed that the signature is strongly up-regulated in macrophage-rich regions and down-regulated in regions with high smooth muscle cell content.\r\nA smaller qPCR biomarker panel and inflammatory composite score (ICS) were developed to facilitate clinical translation of discoveries from gene expression profiling. We found that ICS correlates with histological features related to plaque vulnerability. In addition, ICS is able to separate groups of plaques obtained from symptomatic and asymptomatic patients undergoing carotid endarerectomy. In summary, we identified a robust mRNA biomarker panel associated with histo-pathological as well as clinical hallmarks of vulnerable atherosclerotic plaque. This panel may be used as a diagnostic and prognostic tool in clinical setting to evaluate novel anti-atherosclerotic therapies.
GSE24702 CVMHuman nomodel 290 0 In order to identify potential new biomarkers of atherosclerotic plaque composition we performed a large scale analysis of gene expression patterns in human atherosclerotic lesions. Whole genome expression analysis of 101 peripheral plaques identified a robust gene signature (1514 genes) dominated by inflammatory processes, and cholesterol metabolism and storage genes. Specific pathways enriched in this signature included activation of the Toll-like receptor signaling pathway, T-cell activation, cholesterol efflux, oxidative stress response, inflammatory cytokine production, vasoconstriction and lysosomal activity. Analysis of gene expression in plaque micro-dissected material revealed that the signature is strongly up-regulated in macrophage-rich regions and down-regulated in regions with high smooth muscle cell content.\r\nA smaller qPCR biomarker panel and inflammatory composite score (ICS) were developed to facilitate clinical translation of discoveries from gene expression profiling. We found that ICS correlates with histological features related to plaque vulnerability. In addition, ICS is able to separate groups of plaques obtained from symptomatic and asymptomatic patients undergoing carotid endarerectomy. In summary, we identified a robust mRNA biomarker panel associated with histo-pathological as well as clinical hallmarks of vulnerable atherosclerotic plaque. This panel may be used as a diagnostic and prognostic tool in clinical setting to evaluate novel anti-atherosclerotic therapies.
GSE24818 CVMHuman CVD 40 1 Sub-optimal fetal development is associated with an increased risk of developing cardiovascular disease, type 2 diabetes (T2D) and adiposity later in life. However, definitions of intrauterine growth restriction (IUGR) and small for gestational age (SGA) are based on simple statistical approaches that may misclassify infants with a normal developmental profile and vice versa. We used an unbiased global profiling approach to identify gene expression patterns in umbilical cord tissue from 38 infants and identified a set of 466 genes which separated the subjects into 2 distinct groups – one biased towards lower birth weight and one biased towards normal birth weight. The data suggest that approximately 30% of children of normal size have a molecular profile more typical of impaired fetal development and who may be on a programmed trajectory. Differences in expression between the two groups encompassed 384 upregulated and 82 downregulated genes. Molecular profiling at birth may have utility in identifying markers that potentially reflect antenatal developmental and may be predictive of future phenotypic development after birth. Importantly, it may provide an alternative to the current classification of infants using birth weights.
GSE24988 CVMHuman CVD 116 2 Pulmonary Hypertension (PH) is a frequent complication of Pulmonary Fibrosis (PF). PH can be seen in PF in the abscence of hypoxemia, irrespective of the degree of fibrosis. At the same time, a consistent number of patients with advanced PF never develop PH. The pathogenesis of PH secondary to PF remains unclear. PF patients are often referred to lung transplantation, but they present a higher incidence of pimary graft dysfunction than other diseases. The cause of this is unknown, and the relationship with PH remains unclear.\r\nWe used microarray to identifiy the gene expression profiles in PF patients with and without PH
GSE2508 CVMHuman Obesity 195 6 Microarray analysis comparing gene expression profiles of adipocytes from non-diabetic lean vs non-diabetic obese Pima Indian subjects to identify differentially expressed adipocyte genes with obesity. RNA samples of isolated abdominal subcutaneous adipocytes from 20 lean (10 Males / 10 Females, aged 31±6 year, Body Mass Index 25±3 kg/m2 ) and 19 obese (9M/10F, 29±5y, 55±8 kg/m2 ) subjects were hybridized individually to Affymetrix oligonucleotide arrays HG-U95A, B, C, D, and E.
GSE2510 CVMHuman Obesity 56 2 Microarray analysis comparing gene expression profiles of primary cultured preadipocytes from non-diabetic lean vs non-diabetic obese Pima Indian subjects (a subset of the subjects from the adipocyte genechip project, GSE2508). Primary cultured abdominal subcutaneous preadipocytes from 14 lean (7 Males / 7 Females) and 14 obese (7M/7F) subjects were hybridized individually to Affymetrix oligonucleotide arrays HG-U133A and B.
GSE25401 CVMHuman Obesity 56 1 We used an unbiased systems biology approach to study the regulation of gene expression in human adipose tissue focusing on inflammation. We show that microRNAs play a major role as regulators of CCL2 production in obesity.
GSE25744 CVMHuman CVD 32 1 Two independent protocols for deriving HLCs from hESCs and iPSCs were adopted and further characterization included immunocytochemistry, real-time RT-PCR, and in vitro functional assays. Comparative microarray-based gene expression profiling was conducted on these cells and compared to the transcriptomes of human fetal liver and adult liver progenitors. HLCs derived from hESCs and hiPSCs showed significant functional similarities, similar expression of genes important for liver physiology and common pathways. However, specific differences between the two cell types could be observed.
GSE25910 CVMHuman Obesity 36 2 We used an unbiased systems biology approach to study the regulation of gene expression in human adipose tissue focusing on inflammation. We show that microRNAs play a major role as regulators of CCL2 production in obesity.
GSE26123 CVMHuman Obesity 14 2 To provide a comprehensive understanding of how GC affect adipose tissue and adipocyte function, we analyzed patterns of gene expression after culture of abdominal subcutaneous (sc) and omental (Om))\r\nAdipose tissue of severely obese subjects (3F, 1M) in the presence of insulin or insulin (7 nM) plus dexamethasone (dex, 25 nM) for 7d.
GSE26637 CVMHuman Obesity 20 2 5 arrays from obese insulin-resistant and lean insulin-sensitive females adipose tissue at fasting and after 3h hyperinsulinemia
GSE27034 CVMHuman CVD 37 1 Peripheral arterial disease (PAD) is a relatively common manifestation of systemic atherosclerosis that leads to progressive narrowing of the lumen of leg arteries. Circulating monocytes are in contact with the arterial wall and can serve as reporters of vascular pathology in the setting of PAD. We performed gene expression analysis of peripheral blood mononuclear cells (PBMC) in patients with PAD and controls without PAD to identify differentially regulated genes. We identified 87 genes differentially expressed in the setting of PAD; 40 genes were upregulated and 47 genes were downregulated. We employed an integrated bioinformatics pipeline coupled with literature curation to characterize the functional coherence of differentially regulated genes. Notably, upregulated genes mediate immune response, inflammation, apoptosis, stress response, phosphorylation, hemostasis, platelet activation and platelet aggregation. Downregulated genes included several genes from the zinc finger family that are involved in transcriptional regulation. These results provide insights into molecular mechanisms relevant to the pathophysiology of PAD.
GSE27121 CVMHuman Obesity 70 4 The main aim of this experiment was to investigate gene expression on human adipose tissue after two different 4-week energy-restricted diets. Our questions consisted in understanding how gene expression was linked to clinical parameters of obese patients and whether the two diets were discriminated this data.\r\nThe subjects were randomly allocated, in a cross-over design, to two periods of 4 weeks of an energy restricted isocaloric diet of 1200 kcal as either a conventional diet (LC-CONV) or a special energy restricted diet compensated by proteins (LC-P-LGI). The two nutritional periods were separated by a wash-out interval of 8 weeks. The samples who contain a K in their name correspond to the LC-P-LGI diet while those who contain a C correspond to LC-CONV diet.
GSE27263 CVMHuman CVD 92 5 41 volunteers (male non-smokers) were exposed to formaldehyde (FA) vapors for 4 h per day over a period of 5 working days under strictly controlled conditions. For each exposure day, different exposure concentrations were used in a random order ranging from 0 up to 0.7 ppm. At concentrations of 0.3 ppm and 0.4 ppm, four peaks of 0.6 or 0.8 ppm for 15 min each were applied. During exposure, subjects had to perform bicycle exercises (about 80 W) four times for 15 min. Blood samples, exfoliated nasal mucosa cells and nasal biopsies were taken before the first and after the last exposure. Nasal epithelial cells were additionally sampled 1, 2 and 3 weeks after the end of the exposure period. The alkaline comet assay, the sister chromatid exchange (SCE) test and the cytokinesis-block micronucleus test (CBMNT) were performed with blood samples. The micronucleus test (MNT) was also performed with exfoliated nasal mucosa cells. The expression (mRNA level) of the GSH-dependent formaldehyde dehydrogenase (FDH, identical to alcohol dehydrogenase 5; ADH5; EC 1.2.1.46) was measured in blood samples by quantitative real-time RT-PCR with TaqMan probes. DNA microarray analyses using a full-genome human microarray were performed on blood samples and nasal biopsies of selected subgroups with the highest FA exposure at different days. None of the tests performed showed a biologically significant effect related to FA exposure. Under the experimental conditions of this study, inhalation of FA did not lead to genotoxic effects in peripheral blood cells and nasal mucosa and had no effect on the expression of the FDH gene. Inhalation of FA also did not cause biologically relevant alterations in the expression of genes in a microarray analysis with nasal biopsies and peripheral blood cells.
GSE27503 CVMHuman Obesity 16 2 A major development in the study of obesity is the recognition that the condition is characterised by chronic mild inflammation. Within adipose tissue, this involves the infiltration of macrophages, as well as the direct inflammatory response of the adipocytes and pre-adipocytes. This study has used Agilent whole-genome microarrays to examine the effects of macrophage-conditioned medium on the global inflammatory response of human pre-adipocytes.
GSE27657 CVMHuman Obesity 18 1 Different human adipose tissue depots may have functional differences. Subcutaneous human adipose tissue has been extensively studied, but less is known about other depots. Perithyroid (PT) adipose tissue contains not only white adipocytes but also brown adipocytes. The aim of this study was to compare the expression of brown adipocyte containing perithyroid adipose tissue with s.c. adipose tissue.role in the development of obesity. Expression profiling of adipose tissue may give insights into mechanisms contributing to obesity and obesity-related disorders.
GSE27838 CVMHuman CVD 32 4 Natural Killer cells (NK), a major constituent of innate immune system, have the ability to kill the transformed and infected cells without prior sensitization; can be put to immunotherapeutic use against various malignancies. NK cells discriminate between normal cells and transformed cells via a balance of inhibitory and activating signals induced by interactions between NK cell receptors and target cell ligands. Present study investigates whether expansion of NK cells could augment their anti-myeloma (MM) activity. For NK cell expansion, peripheral blood mononuclear cells from healthy donors and myeloma patients were co-cultured with irradiated K562 cells transfected with 4-1BBL and membrane-bound IL15 (K562-mb15-41BBL). A genome-wide profiling approach was performed to identify gene expression signature in expanded NK (ENK) cells and non-expanded NK cells isolated from healthy donors and myeloma patients. A specific set of genes involved in proliferation, migration, adhesion, cytotoxicity, and activation were up regulated post expansion, also confirmed by flow cytometry. Exp-NK cells killed both allogeneic and autologous primary MM cells more avidly than non-exp-NK cells in vitro. Multiple receptors, particularly NKG2D, natural cytotoxicity receptors, and DNAM-1 contributed to target lysis, via a perforin mediated mechanism. In summary, vigorous expansion and high anti-MM activity both in vitro and in vivo provide the rationale for testing exp-NK cells in a clinical trial for high risk MM.\r\nDifferential gene expression profile in expanded natural killer (ENK) cells and non-expanded natural killer (NK) cells from healthy donors and myeloma patients
GSE27916 CVMHuman Obesity 375 1 Obesity has considerable effects on morbidity and mortality, and the prevalence of obesity has been increasing rapidly worldwide during the past two decades. Even if obesity affects the entire individual, adipose tissue plays a central role in the development of obesity. Expression profiling of adipose tissue may give insights into the mechanisms contributing to obesity and obesity-related disorders.\r\nThe Swedish Obese Subjects (SOS) Sib-Pair Study consists of 154 nuclear families with BMI-discordant sib pairs (BMI difference more than 10 kg/m2) resulting in a study population consisting of 732 subjects. The full SOS Sib-Pair study offspring cohort consists of 425 subjects. Microarray expression analysis in subcutaneous adipose tissue was performed in 375 subjects (262 women and 113 men) of the SOS Sib-Pair offspring cohort.
GSE27949 CVMHuman Obesity 33 10 Adipose tissue abundance relies partly on the factors that regulate adipogenesis, i.e. proliferation and differentiation of adipocytes. While the transcriptional program that initiates adipogenesis is well-known, the importance of microRNAs in adipogenesis is less well studied. We thus set out to investigate whether miRNAs would be actively modulated during adipogenesis and obesity. Several models exist to study adipogenesis in vitro, of which the cell line 3T3-L1 is probably the most well known, albeit not the most physiologically appropriate. We used a microarray strategy to provide a global profile of miRNAs in brown and white primary murine adipocytes (prior to and following differentiation) and evaluated the similarity of the responses to non-primary cell models, through literature data-mining. We found 65 miRNAs regulated during in vitro adipogenesis in primary adipocytes. When we compared our primary adipocyte profiles with those of cell lines reported in the literature, we found a high degree of difference in adipogenesis-regulated miRNAs. We evaluated the expression of 10 of our adipogenesis-regulated miRNAs using real-time qPCR and then selected 5 miRNAs that showed robust expression levels and profiled these by qPCR in subcutaneous adipose tissue of 20 humans with a range of body mass indices (BMI, range=21-48). Of the miRNAs tested, mir-21 was both highly expressed in human adipose tissue and positively correlated with BMI (R2=0.49, p<0.001). In conclusion, we provide the preliminary analysis of miRNAs important for primary cell in vitro adipogenesis and find that the inflammation-associated miRNA, mir-21, is up-regulated in subcutaneous adipose tissue in human obesity.
GSE28038 CVMHuman nomodel 28 0 We profiled gene expression in peripheral blood cells from 28 obese patients by microarray analysis and visceral fat accumulation caused the gene expression proliles especially in circadian rhythm, inflammation, oxidative stress, and immune response.
GSE28358 CVMHuman CVD 65 3 Despite the benefits associated with healthy diets, data on the mechanisms by which these benefits are promoted are scarce. Our aim was to explore the global transcriptomic response of biological pathways related to cardiovascular disease associated with traditional Mediterranean diet (TMD) intervention. The PREDIMED study is a large on-going, parallel, multicentre, randomised, controlled trial aimed at assessing the TMD effect on primary cardiovascular prevention. High cardiovascular risk participants were recruited and assigned to one of the following interventions: 1) TMD plus virgin olive oil (VOO); 2) TMD plus mixed nuts; or 3) low-fat diet (control group). In a sub sample of 30 volunteers of the PREDIMED- Barcelona Sur Centre, gene expression changes in peripheral mononuclear cells, after 3 months of intervention, were assessed by microarray analysis.
GSE28384 CVMHuman Obesity 46 8 Faced by an alarming incidence of metabolic diseases including obesity and type 2 diabetes worldwide, there is an urgent need for effective strategies for preventing and treating these common diseases. The nuclear receptor PPAR? (peroxisome proliferator-activated receptor gamma) plays a crucial role in metabolism. We isolated the amorfrutins from edible parts of the plants Glychyrrhiza foetida and Amorpha fruticosa, and identified these natural products as a new chemical class to treat insulin resistance and diabetes by selectively activating PPAR?. In contrast to existing synthetic PPAR? drugs, the amorfrutins display unique properties by separating insulin sensitization from unwanted side effects. In obese mouse models, amorfrutin treatment significantly improved important metabolic and inflammatory parameters. In summary, PPAR? activation by selective amorfrutins derived from edible biomaterial is a promising approach to combat metabolic diseases and other diseases in which PPAR? is involved in.
GSE28454 CVMHuman CVD 76 2 Monocytes play a central role in the inflammatory response that follows acute myocardial infarction (MI). In order to study phenotypic adaptation of this cell type, we investigated patterns of monocyte gene expression in circulating monocytes at various stages of MI. Circulating monocytes were isolated from venous blood of MI patients at three time points: t1: within 6 hours after onset of chest pain (acute phase), t2: 3 days after MI (subacute phase), t3: 90 days after MI (chronic phase). For comparison, we studied a control group (n=21, data to be submitted later) with stable coronary artery disease.\r\nUsing this transcriptomic analysis, we aimed to provide a more comprehensive reference of monocyte biology following acute MI and to aid in the identification of novel pathways and genes influencing the course of MI.
GSE28603 CVMHuman Obesity 12 3 Hypoxia in adipose tissue is suggested to be involved in the development of a chronic mild inflammation, which in obesity can further lead to insulin-resistance. The effect of hypoxia on gene expression in adipocytes seems to play a central role in this inflammatory response observed in obesity. However, the global impact of hypoxia on transcriptional changes in human adipocytes is unclear. Therefore, we compared gene expression profiles of human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes under normoxic or hypoxic conditions to detect hypoxia-responsive genes in adipocytes by using whole human genome microarrays.
GSE28628 CVMHuman Obesity 9 2 Since the worldwide increase in obesity represents a growing challenge for the health care systems, new approaches are needed to treat obesity and associated disease effectively. The food intake is primarily stored in the adipose tissue and therefore this organ is in focus to develop new anti-obesity treatments.\r\nTo provide a systematic analysis of genes that regulate adipose tissue biology and to establish a target-oriented compound screening, we performed a high throughput siRNA screen with primary (pre)adipocytes, using a druggable siRNA library targeting 7,784 human genes. Beside well known regulators of adipogenesis and neutral lipid storage (like PPAR?, RXR, Perilipin A) the screening revealed a large number of genes which were not previously described in the context of fatty tissue biology. An enrichment of genes was observed for axonemal dyneins. Five out of ten anxonemal dyneins were identified in our primary screen and retested positive with independent siRNAs and cell-donors. Quantitative RT-PCR- and immunoblot analysis revealed that axonemal dyneins are expressed in preadipocytes and maturing adipocytes. Using microarray analysis, we further characterize the remaining genes identified in our primary screen to determine their expression pattern during adipogenesis. In the course of fat cell differentiation, 149 among the 459 positive genes were regulated on the gene expression level. Assuming that an adipogenesis-specific expression pattern is another independent hind, that these genes are involved in neutral lipid storage and/or adipocyte differentiation, we retested this gene-pool with independent siRNAs and cell donors. Finally, to show that the genes identified are per se druggable we performed a proof of principle experiment using an antagonist for one randomly chosen gene. The results showed a very similar phenotype compared to knock-down experiments proofing the druggability.\r\nThus, we identified new adipogenesis-associated genes and those involved in neutral lipid storage. Moreover, by using a druggable siRNA library the screen data provides a very attractive starting point, to identify anti-obesity compounds targeting the adipose tissue.
GSE28686 CVMHuman CVD 40 1 Methcathinone (ephedrone) is relatively easily accessible for abuse. Its users develop an extrapyramidal syndrome and it is not known if this is caused by methcathinone itself, by side-ingredients (manganese), or both. In the present study we aimed to clarify molecular mechanisms underlying this condition. We used microarrays to analyze whole genome gene expression patterns of peripheral blood from 20 methcathinone users and 20 matched controls. Gene expression profile data were analyzed by Bayesian modelling and functional annotation. Of 28,869 genes on the microarrays, 326 showed statistically significant differential expression with FDR adjusted p-values below 0.05. Quantitative RT-PCR confirmed differential expression for the most of the genes selected for validation. Functional annotation and network analysis indicated activation of a gene network that included immunological disease, cellular movement and cardiovascular disease functions (enrichment score 42). As HIV and HCV infections were confounding factors, we performed additional stratification of patients. A similar functional activation of the “immunological disease” category was evident when we compared patients according to injection status (past versus current users, balanced for HIV and HCV infection). However, this difference was not large therefore the major effect was related to the HIV status of the patients. Mn-methcathinone abusers have blood RNA expression patterns that mostly reflect their HIV and HCV infections. However, despite the strong confounding effect from infection, some modest drug abuse effects on gene expression were detected.
GSE28829 CVMHuman CVD 29 1 The objective of this study is to identify genes and pathways involved in the progression of atherosclerotic plaques from early to advanced stage in humans.
GSE29111 CVMHuman CVD 52 2 Coronary artery disease (CAD) remains a leading cause of death worldwide. Acute coronary syndromes (ACS) are the spectrum of diseases arising from coronary atherosclerotic plaque rupture, ranging from unstable angina (UA; clinical symptoms of cardiac ischemia without myocardial necrosis) to myocardial infarction (MI; clinical symptoms of cardiac ischemia with myocardial necrosis).\r\nWe use microrray to identify changes in pathways following MI.This study examines mRNA expression levels in human whole blood at 7 and 30 days post ACS. Patients with MI are compared to those with UA (not healthy controls), thus focusing on differences in mRNA expression due to the acute clinical events rather than underlying atherosclerosis and its treatment.
GSE29409 CVMHuman Obesity 20 3 The objective was to characterize differences in the secretome of human omental compared with subcutaneous adipose tissue using global gene expression profiling. Gene expression was measured using Affymetrix microarrays in subcutaneous and omental adipose tissue (n=5 independent subjects; 10 arrays). Predictive bioinformatic algorithms were employed to identify those differentially expressed genes that code for secreted proteins and to identify common pathways between these proteins. The time course data was not included in the publication and has yet to be published. Patients undergoing surgery were weight stable one month prior to the operation and were not on any medication. All patients provided informed written consent before inclusion in the study which was approved by the North of Scotland Research Ethics Committee (NOSREC).
GSE29410 CVMHuman Obesity 6 1 The objective was to characterize differences in the secretome of human omental compared with subcutaneous adipose tissue using global gene expression profiling. Gene expression was measured using Affymetrix microarrays in subcutaneous and omental adipose tissue (n=3 independent subjects; 6 arrays). Predictive bioinformatic algorithms were employed to identify those differentially expressed genes that code for secreted proteins and to identify common pathways between these proteins. All patients provided informed written consent before inclusion in the study which was approved by the North of Scotland Research Ethics Committee (NOSREC).
GSE29660 CVMHuman Diabetes 5 1 TGF-beta1 is the major cytokine driver of fibrotic scarring observed in diabetic nephropathy and other fibrosis-related diseases. RNA-sequencing offers the potential for more sensitive assessment of the TGF-ß1-driven transcriptome.
GSE29718 CVMHuman Obesity 20 2 The aim of this study was to characterize expression profiles of visceral and subcutaneous adipose tissue in children. Adipose tissue samples were collected from children having elective surgery (n=71, [54 boys], 6.0 +- 4.3 years). Affymetrix microarrays (n=20) were performed to characterize the functional profile and identify genes of interest in adipose tissue. Visceral adipose tissue had an overrepresentation of Gene Ontology themes related to immune and inflammatory responses and subcutaneous adipose tissue had an overrepresentation of themes related to adipocyte growth and development. Likewise, qPCR performed in the whole cohort showed a 30-fold increase in haptoglobin (P < 0.005), 7-fold increase in IL-10 (P < 0.001), 8-fold decrease in VEGF (P < 0.01) and a 28-fold decrease in TBOX15 (P < 0.001) in visceral compared to subcutaneous adipose tissue.The inflammatory pattern in visceral adipose tissue may represent an early stage of the adverse effects of this depot, and combined with chronic obesity, may contribute to increased metabolic and cardiovascular risk.
GSE29819 CVMHuman CVD 38 4 Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy primarily of the right ventricle characterized through fibrofatty replacement of cardiomyocytes. The genetic etiology in ARVC patients is most commonly caused by dominant inheritance and high genetic heterogeneity. Though histological examinations of ARVC affected human myocardium reveals fibrolipomatous replacement, the molecular mechanisms leading to loss of cardiomyocytes are largely unknown.\r\nWe therefore analyzed the transcriptomes of 6 ARVC specimen derived from heart transplantation candidates and compared our findings to 6 non-failing donor hearts (NF) which could not be transplanted for technical reasons. In addition, we compared our findings to 7 hearts from patients with idiopathic dilated cardiomyopathy. From each heart left (LV) and right ventricular (RV) myocardial samples were analyzed by Affymetrix HG-U133 Plus 2.0 arrays, adding up to six sample groups.\r\nUnsupervised cluster analyses of the six sample groups revealed a clear separation of NF and cardiomyopathy samples. However, in contrast to the other samples, unsupervised cluster analyses revealed no distinct expression pattern in LV and RV samples from ARVC-hearts. We further identified differentially expressed transcripts using t-tests and found transcripts separating diseased and NF ventricular myocardium. Of note, in failing myocardium only about 15-16% of the genes are commonly regulated compared to NF samples. In addition both cardiomyopathies are clearly distinct on the transcriptome level. Comparison of the expression patterns between the failing RV and LV using a paired t-test revealed a lack of major differences between LV and RV gene expression in ARVC hearts.
GSE30210 CVMHuman Diabetes 247 1 To unravel genes and molecular pathways involved in the pathogenesis of type 1 diabetes (T1D), we performed genome-wide gene expression profiling of prospective venous blood samples from children developing T1D-associated autoantibodies or progressing towards clinical diagnosis.
GSE30447 CVMHuman fatty liver 16 1 Triglyceride accumulation in nonalcoholic fatty liver (NAFL) results from unbalanced lipid metabolism which, in the liver, is controlled by several transcription factors. The Foxa subfamily of winged helix/forkhead box (Fox) transcription factors comprises three members which play important roles in controlling both metabolism and homeostasis through the regulation of multiple target genes in the liver, pancreas and adipose tissue. In the mouse liver, Foxa2 is repressed by insulin and mediates fasting responses. Unlike Foxa2, however, the role of Foxa1 in the liver has not yet been investigated in detail. In this study, we evaluate the role of Foxa1 in two human liver cell models, primary cultured hepatocytes and HepG2 cells, by adenoviral infection. Moreover, human and rat livers were analyzed to determine Foxa1 regulation in NAFL. Results demonstrate that Foxa1 is a potent inhibitor of hepatic triglyceride synthesis, accumulation and secretion by repressing the expression of multiple target genes of these pathways (e.g., GPAM, DGAT2, MTP, APOB). Moreover, Foxa1 represses the fatty acid transporter FATP2 and lowers fatty acid uptake. Foxa1 also increases the breakdown of fatty acids by inducing HMGCS2 and ketone body synthesis. Finally, Foxa1 is able to largely up-regulate UCP1, thereby dissipating energy and consistently decreasing the mitochondria membrane potential. We also report that human and rat NAFL have a reduced Foxa1 expression, possibly through a protein kinase C-dependent pathway. We conclude that Foxa1 is an antisteatotic factor that coordinately tunes several lipid metabolism pathways to block triglyceride accumulation in hepatocytes. However, Foxa1 is down-regulated in human and rat NAFL and, therefore, increasing Foxa1 levels could protect from steatosis. Altogether, we suggest that Foxa1 could be a novel therapeutic target for NAFL disease and insulin resistance.\r\nTo determine the global impact of Foxa1 on human liver gene transcription, microarray expression analyses were performed in HepG2 cells transfected with Ad-Foxa1 or Ad-Control.
GSE30450 CVMHuman fatty liver 8 1 Triglyceride accumulation in nonalcoholic fatty liver (NAFL) results from unbalanced lipid metabolism which, in the liver, is controlled by several transcription factors. The Foxa subfamily of winged helix/forkhead box (Fox) transcription factors comprises three members which play important roles in controlling both metabolism and homeostasis through the regulation of multiple target genes in the liver, pancreas and adipose tissue. In the mouse liver, Foxa2 is repressed by insulin and mediates fasting responses. Unlike Foxa2, however, the role of Foxa1 in the liver has not yet been investigated in detail. In this study, we evaluate the role of Foxa1 in two human liver cell models, primary cultured hepatocytes and HepG2 cells, by adenoviral infection. Moreover, human and rat livers were analyzed to determine Foxa1 regulation in NAFL. Results demonstrate that Foxa1 is a potent inhibitor of hepatic triglyceride synthesis, accumulation and secretion by repressing the expression of multiple target genes of these pathways (e.g., GPAM, DGAT2, MTP, APOB). Moreover, Foxa1 represses the fatty acid transporter FATP2 and lowers fatty acid uptake. Foxa1 also increases the breakdown of fatty acids by inducing HMGCS2 and ketone body synthesis. Finally, Foxa1 is able to largely up-regulate UCP1, thereby dissipating energy and consistently decreasing the mitochondria membrane potential. We also report that human and rat NAFL have a reduced Foxa1 expression, possibly through a protein kinase C-dependent pathway. We conclude that Foxa1 is an antisteatotic factor that coordinately tunes several lipid metabolism pathways to block triglyceride accumulation in hepatocytes. However, Foxa1 is down-regulated in human and rat NAFL and, therefore, increasing Foxa1 levels could protect from steatosis. Altogether, we suggest that Foxa1 could be a novel therapeutic target for NAFL disease and insulin resistance.\r\nTo determine the global impact of Foxa1 on human liver gene transcription, microarray expression analyses were performed in human hepatocytes transfected with Ad-Foxa1 or Ad-Control.
GSE30528 CVMHuman Diabetes 22 1 We identified 1,700 differentially expressed probesets in DKD glomeruli and 1,831 in diabetic tubuli; 330 probesets were commonly differentially expressed in both compartments. The canonical complement signaling pathway was determined to be statistically differentially regulated in both DKD glomeruli and tubuli and was associated with increased glomerulosclerosis even in an additional set of DKD samples.
GSE30529 CVMHuman Diabetes 22 1 We identified 1,700 differentially expressed probesets in DKD glomeruli and 1,831 in diabetic tubuli; 330 probesets were commonly differentially expressed in both compartments. The canonical complement signaling pathway was determined to be statistically differentially regulated in both DKD glomeruli and tubuli and was associated with increased glomerulosclerosis even in an additional set of DKD samples.
GSE30566 CVMHuman Diabetes 25 1 We identified 1,700 differentially expressed probesets in DKD glomeruli and 1,831 in diabetic tubuli; 330 probesets were commonly differentially expressed in both compartments. The canonical complement signaling pathway was determined to be statistically differentially regulated in both DKD glomeruli and tubuli and was associated with increased glomerulosclerosis even in an additional set of DKD samples.
GSE3059 CVMHuman nomodel 32 0 Background---For decades, plasma lipid levels have been known risk factors of atherosclerosis. Recently, inflammation has gained acceptance as a crucial event in the pathogenesis and development of atherosclerosis. A number of studies have provided some insights into the relationships between the two aspects of atherosclerosis: plasma lipids --- the risk factors, and circulating leukocytes --- the effectors of inflammation. In this study, we investigate the relationships between plasma lipids and leukocytes.\r\nMethods and Results---No significant correlation was found between leukocyte counts and plasma lipid levels in 74 individuals. Profiling and analyzing the leukocyte gene expression of 32 individuals revealed distinctive patterns in response to plasma lipid levels: 1) genes involved in lipid metabolism and in the electron transport chain were positively correlated with triglycerides and low-density lipoprotein cholesterol levels, and negatively correlated with high-density lipoprotein cholesterol levels; 2) genes involved in platelet activation were negatively correlated with high-density lipoprotein cholesterol levels; 3) transcription factors regulating lipidgenesis-related genes were correlated with plasma lipid levels; 4) a number of genes correlated to plasma lipid levels were found located in the regions of known QTLs associated with hyperlipemia.\r\nConclusions--- We discovered interesting patterns of leukocyte gene expression in response to plasma lipid levels. Most importantly, genes involved in lipid metabolism, the electron transportation chain, and platelet activation were found correlated with plasma lipid levels. We suggest that leukocytes respond to changing plasma lipid levels by regulating a network of genes, including genes involved in lipid and fatty acid metabolism, through the activation of key transcription factors, such as sterol regulatory element binding transcription factors and peroxisome proliferative activated receptors.
GSE30718 CVMHuman CKD 47 1 Microarray analysis of human kidneys with acute kidney injury (AKI) has been limited because such kidneys are seldom biopsied. However, all kidney transplants experience AKI, and early kidney transplants without rejection are an excellent model for human AKI: they are screened to exclude chronic kidney disease, frequently biopsied, and have extensive follow-up. We used histopathology and microarrays to compare indication biopsies from 28 transplants with AKI to 11 pristine protocol biopsies of stable transplants. Kidneys with AKI showed increased expression of 394 injury-repair response associated transcripts, including many known epithelial injury molecules (e.g. ITGB6, LCN2), tissue remodeling molecules (e.g. VCAN), and inflammation molecules (S100A8, ITGB3). Many other genes also predict the phenotype, depending on statistical filtering rules, including AKI biomarkers as HAVCR1 and IL18. Most mouse orthologs of the top injury-repair transcripts were increased in published mouse AKI models. Pathway analysis of the injury-repair transcripts revealed similarities to cancer, development, and cell movement. The injury-repair transcript score AKI kidneys correlated with reduced function, future recovery, brain death, and need for dialysis, but not future graft loss. In contrast, histologic features of "acute tubular injury" did not correlate with function or with the molecular changes. Thus the injury-repair associated transcripts represent a massive coordinate injury-repair response of kidney parenchyma to AKI, similar to mouse AKI models, and provide an objective measure for assessing the severity of AKI in kidney biopsies and validation for the use of many AKI biomarkers.
GSE31901 CVMHuman Obesity 56 5 Dietary fat quality may influence skeletal muscle lipid handling and fat accumulation, thereby modulating insulin sensitivity. Objective: To examine acute effects of meals with various fatty acid (FA) compositions on skeletal muscle FA handling and postprandial insulin sensitivity in obese insulin resistant men. Design: In a single-blinded randomized crossover study, 10 insulin resistant men consumed three high-fat mixed-meals (2.6MJ). Meals were high in saturated FA (SFA), in monounsaturated FA (MUFA) or in polyunsaturated FA (PUFA). Fasting and postprandial skeletal muscle FA handling were examined by measuring arterio-venous concentration differences across forearm muscle. [2H2]-palmitate was infused intravenously to label endogenous triacylglycerol (TAG) and FFA in the circulation and [U-13C]-palmitate was added to the meal to label chylomicron-TAG. Skeletal muscle biopsies were taken to assess intramuscular lipid metabolism and gene expression. Results: Insulin and glucose responses (AUC) after SFA meal were significantly higher compared with PUFA meal (p=0.003 and 0.028, respectively). Uptake of TAG-derived FA was significantly lower in the early postprandial phase after PUFA meal as compared with other meals (AUC60-120, p<0.001). The PUFA meal induced less transcriptional downregulation of oxidative pathways compared with other meals. The fractional synthetic rate was higher in DAG and PL fraction after MUFA and PUFA meal. Conclusion: Intake of a PUFA meal reduced TAG-derived skeletal muscle FA uptake, which was accompanied by higher postprandial insulin sensitivity and a tendency towards a higher muscle lipid turnover. These data suggest that the effects of replacement of SFA by PUFA may contribute to less muscle lipid uptake and may be therefore protective against the development of insulin resistance.
GSE32357 CVMHuman Obesity 20 1 Resveratrol is a naturally occurring compound that profoundly affects energy metabolism and mitochondrial function and serves as a calorie restriction mimetic, at least in animal models of obesity. Here we treated 10 healthy, obese men with placebo and 150 mg/day resveratrol in a randomized double-blind cross-over study for 30 days. Resveratrol supplementation significantly reduced sleeping- and resting metabolic rate. In muscle, resveratrol activated AMPK, increased SIRT1 and PGC-1alpha protein levels, increased citrate synthase activity, and improved muscle mitochondrial respiration on a fatty acid-derived substrate. Furthermore, resveratrol elevated intramyocellular lipid levels, and decreased intrahepatic lipid content, circulating glucose, triglycerides, alanine-aminotransferase, and inflammation markers. Systolic blood pressure dropped and HOMA index improved after resveratrol. In the postprandial state, adipose tissue lipolysis and plasma fatty acid and glycerol decreased. In conclusion, we demonstrate that 30 days of resveratrol supplementation induces profound metabolic changes in obese subjects, mimicking the effects of calorie restriction.
GSE32443 CVMHuman Obesity 9 2 Synthetic selective thyroid hormone (TH) receptor (TR) modulators (STRMs) exhibit beneficial effects on dyslipidemias in animals and humans and reduce obesity, fatty liver and insulin resistance in preclinical animal models. STRMs differ from native THs in preferential binding to the TRß subtype versus TRa, increased uptake into liver and reduced uptake into other tissues. However, selective modulators of other nuclear receptors (NRs) exhibit important gene-selective actions which have been attributed to differential effects on receptor conformation and dynamics and these effects can have profound influences in animals and humans. While there are suggestions that STRMs could exhibit such gene-specific actions, the extent to which these effects are actually observed in vivo has not been explored. Here, we show that saturating concentrations of the main active form of TH, triiodothyronine (T3), and the prototype STRM GC-1 induce identical gene-sets in livers of euthyroid and hypothyroid mice and a human cultured hepatoma cell line that only expresses TRß, HepG2. We find one case in which GC-1 exhibits a modest gene-specific reduction in potency versus T3, at angiopoietin-like factor 4 (ANGPTL4) in HepG2. Investigation of the latter effect confirms that GC-1 acts through TRß to directly induce this gene. However, this gene-selective GC-1 activity is not related to unusual T3 response element (TRE) sequence, unlike previously documented promoter-selective STRM actions. Together, our data suggest that T3 and GC-1 exhibit almost identical gene regulation properties and that gene-selective actions of GC-1 and similar STRMs will be subtle and rare.
GSE32512 CVMHuman nomodel 204 0 Objective: Insulin regulates amino acid metabolism. We investigated whether glycemia and 43 genetic risk variants for hyperglycemia/type 2 diabetes affect amino acid levels in a large population-based cohort. Subjects and Methods: A total of 9,371 non-diabetic or newly-diagnosed type 2 diabetic Finnish men from the population-based METSIM Study were studied. Proton NMR spectroscopy was used to measure plasma levels of 8 amino acids. Genotyping of 42 SNPs and mRNA microarray analysis from 200 subcutaneous adipose tissue samples were performed. Results: Increasing fasting and/or 2-hour plasma glucose levels were associated with increasing levels of alanine, valine, leucine, isoleucine, phenylalanine and tyrosine, and decreasing levels of histidine and glutamine. We also found significant correlations between insulin sensitivity (Matsuda ISI) and expression of genes regulating amino acid metabolism. Only one SNP (rs780094 in GCKR) of the 42 risk SNPs for type 2 diabetes or hyperglycemia was significantly associated with the levels of alanine, isoleucine, and glutamine. Conclusions : We observed that the levels of branched-chain, aromatic amino acids and alanine increased and the levels of glutamine and histidine decreased with increasing glycemia. These associations seemed to be mediated by insulin resistance, at least in part. GCKR rs780094 was significantly associated with several amino acids.
GSE32575 CVMHuman Obesity 48 2 Low-grade chronic inflammation plays an important role in the development of obesity and obesity-associated disorders such as insulin resistance, type 2 diabetes, the metabolic syndrome and atherosclerosis. One possible link between obesity and inflammation is the enhanced activation of circulating monocytes making them more prone to infiltration into the adipose and vascular tissues of obese persons. Furthermore, weight loss after bariatric surgery is associated with less inflammation. Transcriptome analysis of circulating monocytes from control and obese patients before and after bariatric surgery will potentially provide insights into the pathophysiology of obesity and associated disorders and supply biomarkers for diagnostic purpose. The cohort comprised 6 lean age-matched controls (BMI: 20.3±0.5 kg/m2, mean±SEM) and 18 obese individuals without clinical symptoms of cardiovascular disease (BMI: 45.1±1.4 kg/m2, P<0.001 compared with lean controls). These 18 morbidly obese subjects were referred to our hospital for bariatric surgery. Before they were included, individuals were evaluated by an endocrinologist, an abdominal surgeon, a psychologist and a dietician. Only after multidisciplinary deliberation, the selected patients received a laparoscopic Roux-en-Y gastric bypass. CD14+ monocytes were collected before and three months after bariatric surgery (BMI: 37.5±1.3 kg/m2, P<0.001 compared with before weight loss), total RNA was extracted and subjected to genome-wide expression analysis.
GSE32874 CVMHuman Diabetes 20 3 We have determined the whole genome sequence of an individual at high accuracy and performed an integrated analysis of omics profiles over a 1.5 year period that included healthy and two virally infected states. Omics profiling of transcriptomes, proteomes, cytokines, metabolomes and autoantibodyomes from blood components have revealed extensive, dynamic and broad changes in diverse molecular components and biological pathways that occurred during healthy and disease states. Many changes were associated with allele- and edit-specific expression at the RNA and protein levels, which may contribute to personalized responses. Importantly, genomic information was also used to predict medical risks, including Type II Diabetes (T2D), whose onset was observed during the course of our study using standard clinical tests and molecular profiles, and whose disease progression was monitored and subsequently partially managed. Our study demonstrates that longitudinal personal omics profiling can relate genomic information to global functional omics activity for physiological and medical interpretation of healthy and disease states.
GSE32909 CVMHuman Diabetes 180 2 Objective was to examine acute gene expression responses to physiologic oral glucose ingestion in human circulating leukocytes. Microarray study of human circulating leukocytes sampled before, 1 hour after and 2 hours after glucose ingestion was performed. The present study demonstrated 36 genes which showed acute gene expression change in human leukocytes within 1 hour after glucose ingestion and suggest that leukocytes participate in the inflammatory process induced by acute hyperglycemia.
GSE33463 CVMHuman CVD 140 4 The hypothesis tested in this study was that chronic exposure of PBMCs to a hypertensive environment in remodeled pulmonary vessels would be reflected by specific transcriptional changes in these cells.\r\nThe transcript profiles of PBMCs from 30 idiopathic pulmonary arterial hypertension patients (IPAH), 19 patients with systemic sclerosis without pulmonary hypertension (SSc), 42 scleroderma-associated PAH patients (SSc-PAH), and 8 patients with SSc complicated by interstitial lung disease and PH (SSC-PH-ILD) were compared to the gene expression profiles of PBMCs from 41 healthy individuals.
GSE34007 CVMHuman Obesity 8 1 Obesity is characterised by expansion of white adipose tissue, accompanied by an inflamatory response. It has been proposed that the inflammatory state observed may be linked to relative hypoxia in clusters of adipocytes distant from vasculature. Adipose tissue hypoxia has been observed in both animal models and human studies in obesity, and has been linked to insulin resistance. This study has used Agilent whole-genome microarrays to examine the effects of acute hypoxia on the global gene expression in human adipocytes.
GSE34198 CVMHuman CVD 97 1 Peripheral blood samples of patients with acute myocardial infarction were matched with those of control patients to identify possible differences in corresponding gene expression profiles. The controls were matched to cases based on gender, age, status of diabetes mellitus and smoking status. Six months cardiovascular survival status of the cases was used to identify two distinct subgroups among the cases. Linear models for microarray data (‘limma’) were employed to identify differential gene expression. Shrunken centroids technique helped in identifying the subsets of differentially expressed genes with predictive properties in independent samples. Predictive properties were evaluated using bootstrap sampling. Using the limma modeling with the log-fold change threshold of one (clinical significance) and Storey’s q-value approach (statistical significance), sixty transcripts were found to be both clinically and statistically differentially expressed among the cases not surviving the follow-up period relative to controls, while no such transcripts were observed among other surviving cases. The two subgroups of cases exhibited fourteen differentially expressed transcripts. Predictive modeling indicated sixteen out of sixty transcripts to best discriminate between the controls and cases who died during the follow-up period from cardiovascular causes, while for the surviving cases the already non-significant set of transcripts could not be further reduced. Eleven out of fourteen transcripts were found to best discriminate between the two groups of cases using shrunken centroids. The study identified genes, which were differentially expressed during the acute myocardial infarction, including those associated with short-term fatality of the cases.
GSE34457 CVMHuman CVD 43 3 Molecular Signatures of cardiac defects in Down syndrome lymphoblastoid cell lines. In this study, we want to identify genes and pathways specifically dysregulated in atrioventricular septal defect and /or atrial septal defect + ventricular septal defect in case of trisomy 21.
GSE34788 CVMHuman Obesity 120 4 The rates of obesity and sedentary lifestyle are on a dramatic incline, with associated detrimental health effects among women in particular. Although exercise prescriptions are useful for overcoming these problems, success can be hampered by differential responsiveness among individuals in cardiovascular fitness indices (i.e., improvements in strength, lipids, VO2max). Genetic factors appear to play an important role in determining this inter-individual variation in responsiveness. We performed microarray analyses on mRNA in whole blood from 60 sedentary women from a multi-ethnic cohort who underwent 12 weeks of exercise, to identify gene subsets that were differentially expressed between individuals who experienced the greatest and least improvements in fitness based upon a composite fitness score index. We identified 43 transcripts in 39 unique genes (FDR<10%; FC>1.5) whose expression increased the most in “high” versus “low” premenopausal female responders. Several (TIGD7, UQCRH, PSMA6, WDR12, TFB2M, USP15) have reported associations with fitness-related phenotypes. Bioinformatic analysis of the 39 genes identified 4 miRNAs whose expression has been linked to cardiovascular diseases (ANKRD22: miR-637, LRRFIP1: miR-132, PRKAR2B: miR-92a, RSAD2:miR-192). These 39 genes were enriched in 6 biological pathways, including the oxidative phosphorylation pathway (p=8.08 x 10-3). Two genes, LRRFIP1 and SNORD30, were also identified with lower expression in high responding postmenopausal women. In summary, we identified gene signatures based on mRNA analysis that define responsiveness to exercise in a largely minority-based female cohort. Importantly, this study validates several genes/pathways previously associated with exercise responsiveness and extends these findings with additional novel genes.
GSE34822 CVMHuman CVD 32 1 The identification of classic risk factors for coronary artery disease unveiled pathophysiologic mechanisms of atherosclerosis. Among them, inflammation as a systemic process measurable in peripheral blood plays a central role in plaque progression. However, other mechanisms of plaque progression remain to be fully understood. Therefore, this study sought to further investigate systemic correlates of plaque progression by global gene expression in peripheral blood.\r\nMicrorarray gene expression analysis revealed 93 genes differentially expressed between the groups, of which 23 genes have no known function. Among the remaining 70 genes, 10 (14%) were identified to be associated with progenitor and pluripotent cells whereas only 3 genes (4%) had been associated with atherosclerosis. A risk prediction gene signature was developed by a multivariable statistical approach model integrating comprehensive laboratory and clinical patient data. This signature identified plaque progression with 81% sensitivity and 80% specificity (AUC: 0.86) for new patients, as estimated by resampling techniques. Array results were validated by qPCR for the genes ankyrin-2 (ANK2) and glutathione S-transferase theta 1 (GSTT1). In conclusion, patients with pogressive coronary artery disease despite good risk factor control exhibit particular gene expression patterns in peripheral blood. Understanding the functional implications of the observed changes might help to design new approaches to control atherosclerosis progression.
GSE34904 CVMHuman CVD 40 3 The transcription factors Nanog, Oct4 and Sox2 are the master regulators of pluripotency in mouse embryonic stem cells (mESCs), however, their functions in human ESCs (hESCs) have not been rigorously defined. Here we show that the requirements for NANOG, OCT4 and SOX2 in hESCs differ from those in mESCs. Both NANOG and OCT4 are required for self-renewal and repress differentiation. OCT4 controls both extraembryonic and epiblast-derived cell fates in a BMP4-dependent manner. OCT4-depleted hESCs commit to trophectoderm and primitive endoderm in the presence of BMP4, but undergo neuroectoderm differentiation in the absence of BMP4. NANOG represses neuroectoderm and neural crest commitment, but has little or no effect on the other lineages. We find that SOX2 is not required for self-renewal because it is redundant with SOX3, which is induced in SOX2-depleted hESCs. Simultaneous depletion of both SOX2 and SOX3 induces differentiation into the primitive streak. Unexpectedly, we identify significant variability in the usage of pluripotency factors by individual hESC lines, suggesting that the pluripotency network is remodelled to support a continuum of developmental states. Our study revises the general view of how NANOG, OCT4 and SOX2 orchestrate self-renewal in hESCs.
GSE35197 CVMHuman Fatty-liver 4 2 The association between hyper-inflammatory states and numerous diseases is widely recognized, but our understanding of the molecular strategies that have evolved to prevent uncontrolled activation of inflammatory responses remains incomplete. Here, we report a critical, non-transcriptional role of GPS2 as a guardian against hyperstimulation of TNFA-induced gene program. GPS2 cytoplasmic actions are required to specifically modulate RIP1 ubiquitylation and JNK activation by inhibiting TRAF2/Ubc13 enzymatic activity. In vivo relevance of GPS2 anti-inflammatory role is confirmed by inhibition of TNFA target genes in macrophages and by improved insulin signaling in the adipose tissue of aP2-GPS2 transgenic mice. As the non-transcriptional role is complemented by GPS2 functioning as positive and negative cofactor for nuclear receptors, in vivo overexpression also results in elevated circulating level of resistin and development of hepatic steatosis. Together, these studies define GPS2 as a molecular guardian required for precise control of inflammatory responses involved in immunity and homeostasis.
GSE35296 CVMHuman Diabetes 10 1 We have used RNA-seq to identify transcripts, including splice variants, expressed in human islets of Langerhans under control condition or following exposure to the pro-inflammatory cytokines interleukin-1ß (IL-1ß) and interferon-? (IFN-?). A total of 29,776 transcripts were identified as expressed in human islets. Expression of around 20% of these transcripts was modified by pro-inflammatory cytokines, including apoptosis- and inflammation-related genes. Chemokines were among the transcripts most modified by cytokines. Interestingly, 35% of the genes expressed in human islets undergo alternative splicing as annotated in RefSeq, and cytokines caused substantial changes in spliced transcripts. Nova1, previously considered a brain-specific regulator of mRNA splicing, is expressed in islets. 25/41 of the candidate genes for type 1 diabetes are expressed in islets, and cytokines modified expression of several of these transcripts.
GSE35347 CVMHuman CVD 33 2 The difficulty associated with generating induced pluripotent stem cells (iPSC) from patients with chromosomal instability syndromes suggests the cellular DNA damage response poses a barrier to reprogramming. Here we demonstrate that fibroblasts from patients with ataxia-telangiectasia (A-T) can be reprogrammed to bona-fide iPSC, albeit at a reduced efficiency. A-T iPSC display defective radiation-induced signaling, radiosensitivity and cell cycle checkpoint defects. Bioinformatic analysis of gene expression in the A-T iPSC identifies abnormalities in DNA damage signaling pathways as well as changes in mitochondrial and pentose phosphate pathways. A-T iPSC can be differentiated into functional neurons and thus represent a suitable model system to investigate A-T associated neurodegeneration. Collectively our data show that iPSC can be generated from a chromosomal instability syndrome and that these cells can be used to discover early developmental consequences of ATM deficiency, such as altered mitochondrial function, that may be relevant to A-T pathogenesis and amenable to therapeutic intervention.
GSE35411 CVMHuman Obesity 26 2 Background. Differential gene expression in adipose tissue during diet-induced weight loss followed by a weight stability period is not well characterized. Markers of these processes may provide a deeper understanding of the underlying mechanisms. Objective. To identify differentially expressed genes in human adipose tissue during weight loss and weight maintenance after weight loss. Design. RNA from subcutaneous abdominal adipose tissue from nine obese subjects was obtained and analyzed at baseline, after weight reduction on a low calorie diet (LCD), and after a period of group therapy in order to maintain weight stability. Results. Subjects lost 18.8 + 5.4% of their body weight during the LCD and maintained this weight during group therapy. Insulin sensitivity (HOMA) improved after weight loss with no further improvement during weight maintenance. Cyclin-dependent kinase inhibitor 2B (CDKN2B) and JAZF zinc finger 1 (JAZF1), associated with type 2 diabetes, were downregulated. We could also confirm the downregulation of candidates for obesity and related traits, such as tenomodulin (TNMD) and matrix metallopeptidase 9 (MMP9), with weight loss. The expression of other candidates, such as cell death-inducing DFFA-like effector A (CIDEA) and stearoyl-CoA desaturase (SCD) were upregulated during weight loss but returned to baseline levels during weight maintenance. Conclusion. Genes in the adipose tissue are differentially expressed during weight loss and weight maintenance after weight loss. Genes that show sustained regulation may be of potential interest as markers of the beneficial effects of weight loss whereas others seem to be primarily involved in the process of weight loss itself.
GSE35710 CVMHuman Obesity 48 1 Obesity has considerable effects on morbidity and mortality and the prevalence of obesity has been increasing rapidly worldwide during the past two decades. Even if obesity affects the entire individual, adipose tissue play a central role in the development of obesity. Expression profiling of adipose tissue may give insights into mechanisms contributing to obesity and obesity-related disorders.\r\n24 obese subjects (6 women and 18 men, BMI 37.6 ± 4.9) received a very low calorie diet (450 kcal/d, Cambridge diet or Modifast) for 16 weeks. On average, patients lost 27.7 kg during the diet.
GSE35725 CVMHuman Diabetes 114 3 The complex milieu of inflammatory mediators associated with many diseases is often too dilute to directly measure in the periphery, necessitating development of more sensitive measurements suitable for mechanistic studies, earlier diagnosis, guiding selection of therapy, and monitoring interventions. Previously, we determined that plasma of recent-onset (RO) Type 1 diabetes (T1D) patients induce a proinflammatory transcriptional signature in fresh peripheral blood mononuclear cells (PBMC) relative to that of unrelated healthy controls (HC). Here, using an optimized cryopreserved PBMC-based protocol, we analyzed larger RO T1D and HC cohorts. In addition, we examined T1D progression by looking at longitudinal, pre-onset and longstanding T1D samples.
GSE36418 CVMHuman CVD 78 1 This study sought correlates of relapse tendency in TTP by examining gene expression profiles in peripheral blood leukocytes from patients with acquired ADAMTS13-deficient TTP in remission and matched healthy controls for global gene expression and autoantibodies.
GSE36791 CVMHuman CVD 61 1 In the present study we aimed to investigate the systemic response to a rupture of intracranial aneurysms by an analysis of global gene expression profiles in peripheral blood cells. In addition, we sought to determine whether this approach could provide biomarkers related to clinical status of subarachnoid hemorrhage patients.
GSE37025 CVMHuman Diabetes 235 8 Background: Blocking the action of the pro-inflammatory cytokine interleukin-1 (IL-1) reduces beta-cell secretory dysfunction and apoptosis in vitro, diabetes incidence in animal models of Type 1 diabetes mellitus (T1D), and glycaemia via improved beta-cell function in patients with T2D. We hypothesised that anakinra, a recombinant human IL-1 receptor antagonist, improves beta-cell function in patients with new-onset T1D. Methods: In an individually randomised, two-group parallel trial involving 14 European tertiary referral centers, 69 patients aged 18-35 with T1D, < 12 weeks of symptoms, and standard mixed meal test (MMT) stimulated C-peptide = 200 pM were enrolled between January, 2009 and July, 2011 and assigned by centralised computer-generated blocked randomisation with locked computer-file concealment to treatment with 100 mg anakinra (n=35) subcutaneously once daily or placebo (n=34) for 9 months as add-on to conventional therapy. Participants and care-givers, but not data monitoring unit, were masked to group assignment. The primary end-point was change in the two-hour area-under-the-curve C-peptide response to MMT, and secondary end-points changes in insulin requirements, glycaemia, and inflammatory markers at one, three, six, and nine months. Findings: The study was prematurely terminated due to slow accrual and is closed to follow-up. No interim analysis was performed. Ten patients withdrew in the anakinra and eight in the placebo arm, leaving 25 and 26 patients to be analysed, respectively. There was no statistical difference in adverse event category reporting between arms. Interpretation: Anakinra-treatment in T1D was safe, but the trial failed to meet primary and secondary outcome measures.
GSE37031 CVMHuman fatty liver 15 1 The mechanisms underlying the progression of non-alcoholic steatohepatitis (NASH) are not completely elucidated. In this study we have integrated gene expression profiling of liver biopsies of NASH patients with translational studies in a mouse model of steatohepatitis and with pharmacological interventions in isolated hepatocytes to identify a novel mechanism implicated in the pathogenesis of NASH. By using high-density oligonucleotide microarray analysis we identified a significant enrichment of known genes involved in the multi-step catalysis of long chain polyunsaturated fatty acids, including delta-5 and 6 desaturases. A combined inhibitor of delta-5 and delta-6 desaturases significantly reduced intracellular lipid accumulation and inflammatory gene expression in isolated hepatocytes. Gas chromatography analysis revealed impaired delta-5 desaturase activity toward the omega-3 pathway in livers from mice with high-fat diet (HFD)-induced NASH. Consistently, restoration of omega-3 index in transgenic fat-1 mice expressing an omega-3 desaturase, which allows the endogenous conversion of omega-6 into omega-3 fatty acids, produced a significant reduction in hepatic insulin resistance, hepatic steatosis, macrophage infiltration and necroinflammatory liver injury, accompanied by attenuated expression of genes involved in inflammation, fatty acid uptake and lipogenesis. These results were comparable to those obtained in a group of mice receiving a HFD supplemented with EPA/DHA. Of interest, hepatocytes from fat-1 mice or supplemented with EPA exhibited synergistic anti-steatotic and anti-inflammatory actions with the delta-5/ delta-6 inhibitor. Conclusion: These findings indicate that both endogenous and exogenous restoration of the hepatic balance between omega-6 and omega-3 fatty acids and/or modulation of desaturase activities exert preventive actions in NASH.
GSE37171 CVMHuman CKD 115 1 Renal failure is characterized by important biological changes resulting in profound pleomorphic physiological effects termed “uremia”, whose molecular causation is not well understood. The data was used to study gene expression changes in uremia using whole genome microarray analysis of peripheral blood from subjects with end-stage renal failure (n=63) and healthy controls (n=20) to obtain insight into the molecular and biological causation of this syndrome.
GSE37324 CVMHuman Obesity 26 3 Differences in the inherent properties of undifferentiated fat cell progenitors may contribute to the biological specificity of the abdominal subcutaneous (Sc) and visceral omental (V) fat depots. In this study, the biological characteristics of three distinct subpopulations of adipose tissue-derived stem cells (ASC), i.e. ASCSVF, ASCBottom and ASCCeiling isolated from Sc and V adipose tissue biopsies of non-obese subjects, were investigated. Genome-wide differential gene expression analysis followed by quantitative RT-PCR and analysis of cytokines in the ASC-derived conditioned medium were performed. By analysis of 28,869 annotated genes, 1,019 genes resulted differentially expressed between Sc-ASC and V-ASC. Within the Sc-ASC and V-ASC populations, 546 and 1,222, respectively, were the genes differentially expressed among ASCSVF, ASCBottom and ASCCeiling. A far more striking difference was found when the hierarchical clusters analysis was performed comparing each Sc-ASC with its own homologous V-ASC subset. mRNA levels of HoxA5, Tbx15, PI16, PITPNC1, FABP5, IL-6, IL-8, MCP-1, VEGF, MMP3, TFPI2, and ANXA10 were significantly different between Sc-ASC and V-ASC. Of the 27 cytokines measured, 14 (IL-2, IL-4, IL-5 IL-7, IL-9, IL-10, IL12, IL13, MIP1-a, MIP1-ß, PDGF-??, FGFbasic, GM-CSF, IP-10) were not released, whereas 13 were expressed (IL-1beta, IL-1ra, IL-15, IL-17, G-CSF, IFN?, RANTES, TNF-a, Eotaxin, IL-8, MCP-1, VEGF, IL-6), and of these, MCP-1, Eotaxin, IL-1ra, FGFbasic, IL-6, IL-8, G-CSF, and VEGF were significantly different among ASCSVF, ASCCeiling and ASCBottom of the two adipose tissue depots. These results demonstrate the existence of genetically and functionally heterogeneous fat-derived ASC populations, which may add to the complexity and specificity of Sc and V adipose tissue in humans.
GSE37558 CVMHuman CVD 32 5 Background: Ectopic vascular calcifications represent a major clinical problem associated with cardiovascular disease and mortality. However, the mechanisms underlying pathological vascular calcifications are largely unknown hampering the development of therapies to tackle this life threatening medical condition.\r\nResults: In order to gain insight into the genes and mechanisms driving this pathological calcification process we analyzed the transcriptional profile of calcifying vascular smooth muscle cells (C-VSMCs). These profiles were compared to differentiating osteoblasts, cells that constitute their physiological calcification counterparts in the body. Overall the transcriptional program of C-VSMC and osteoblasts did not overlap. Several genes, some of them relevant for bone formation, were distinctly modulated by C-VSMCs which did not necessarily lose their smooth muscle cell markers while calcifying. Bioinformatics gene clustering and correlation analysis disclosed limited bone-related mechanisms being shared by two cell types. Extracellular matrix (ECM) and biomineralization genes represented common denominators between pathological vascular and physiological bone calcifications. These genes constitute the strongest link between these cells and represent potential drivers for their shared end-point phenotype.\r\nConclusions: the analyses support the hypothesis that VSMC trans-differentiate into C-VSMCs keeping their own identity while using mechanisms that osteoblasts use to mineralize. The data provide novel insights into groups of genes and biological processes shared in MSC and VSMC osteogenic differentiation. The distinct gene regulation between C-VSMC and osteoblasts might hold clues to find cell-specific pathway modulations, opening the possibility to tackle undesired vascular calcifications without disturbing physiologic bone formation and vice versa.
GSE37761 CVMHuman CVD 28 9 Early development of mammalian embryos occurs in an environment of relative hypoxia. Nevertheless, human embryonic stem cells (hESC), which are derived from the inner cell mass of blastocyst, are routinely cultured under the same atmospheric conditions (21% O2) as somatic cells. We hypothesized that O2 levels modulate gene expression and differentiation potential of hESC, and thus, we performed gene profiling of hESC maintained under normoxic or hypoxic (1% or 5% O2) conditions. Our analysis revealed that hypoxia downregulates expression of pluripotency markers in hESC but increases significantly the expression of genes associated with angio- and vasculogenesis including vascular endothelial growth factor and angiopoitein-like proteins. Consequently, we were able to efficiently differentiate hESC to functional endothelial cells (EC) by varying O2 levels; after 24 hours at 5% O2, more than 50% of cells were CD34+. Transplantation of resulting endothelial-like cells improved both systolic function and fractional shortening in a rodent model of myocardial infarction. Moreover, analysis of the infarcted zone revealed that transplanted EC reduced the area of fibrous scar tissue by 50%. Thus, use of hypoxic conditions to specify the endothelial lineage suggests a novel strategy for cellular therapies aimed at repair of damaged vasculature in pathologies such as cerebral ischemia and myocardial infarction.
GSE38642 CVMHuman Diabetes 63 1 Close to 50 genetic loci have been associated with type 2 diabetes (T2D), but they explain only 15% of the heritability.\r\nIn an attempt to identify additional T2D genes, we analyzed global gene expression in human islets from 63 donors.
GSE39576 CVMHuman Obesity 24 4 Breaking up prolonged sitting has been shown to be beneficially associated with cardio-metabolic risk markers in both observational and intervention studies. We aimed to define the acute transcriptional events induced in skeletal muscle by breaks in sedentary time.\r\nOverweight/obese adults participated in a randomized three-period, three-treatment cross-over trial in an acute setting (5 hours): seated position with no activity, seated with 2-minute bouts of light- or moderate-intensity treadmill walking every 20 minutes. Vastus lateralis biopsies were obtained in 8 of the 19 participants after each treatment and gene expression examined using microarrays validated with real-time qPCR.
GSE40231 CVMHuman CVD 278 4 Tissue samples have been isolated during corornary artery by-pass grafting (CABG)surgery from the atheroscelrotic arterial wall (AAW, aortic root puncture for proxmal ligation of by-pass vessel), non-atherosclertoci arterial wall (NAAW, distal part of mammary artery used a graft for LAD), liver, skeletal muscle (Recturs m), pericardial mediastinal visceral fat) in CAD patients. Carotid lesions samples from 25 validation patients.\r\nWe used microarrays to measure global gene expression in these tissues to cluster groups of functionally associated genes and then, second step clustering of patients within each cluster to link clusters to patient phenotypes primarily coronary stenosis (CAD) and Intima media thickness (IMT) in carotid stenosis patients. .
GSE41036 CVMHuman CVD 73 2 In Coronary Artery Bypass Grafting (CABG), the combined use of Left or Right Internal Mammary Artery (LIMA or RIMA) -collectively known as Bilateral IMAs (BIMAs)- provides a survival advantage over the LIMA alone. Several studies analyzed the gene expression in LIMAs and other conduits, however they either used a candidate gene approach or analyzed a small number of samples. Additionally, RIMA has never been analyzed compared to LIMA. Here we report a genome-wide transcriptional analysis of BIMA to investigate the expression profile of these conduits in patients undergoing CABG. Marginal differences were reported between LIMA and RIMA (p <0.05) using a linear model for microarray data. Ingenuity Pathway Assist (IPA) analysis found no consistent set of over-represented pathways and no trends in patterns of gene expression. As expected, in comparing the BIMAs to the aorta, we found differences in pathways and processes associated with atherosclerosis, inflammation, and cell signaling. Although evidence in favor of the use of BIMA in CABG has been available for over a decade, their routine use in clinical practice remains very low accounting for only 4% of CABG procedures in the US. Despite differences in embryologic development, our genome-wide transcriptional analysis, show marginal differences between LIMA and RIMA. Taken together, clinical and genomic analyses provide evidences that could impact the independent or combined use of the BIMAs as a conduit in CABG.
GSE41168 CVMHuman Obesity 140 10 Resveratrol has been reported to improve metabolic function in metabolically-abnormal rodents and humans, but has not been studied in non-obese people with normal glucose tolerance. We conducted a randomized, double-blind, placebo-controlled trial to evaluate the metabolic effects of 12 weeks of resveratrol supplementation (75 mg/day) in non-obese, postmenopausal women with normal glucose tolerance. Although resveratrol supplementation was well-tolerated and increased plasma resveratrol concentration without adverse effects, it did not change body composition, resting metabolic rate, plasma lipids, or inflammatory markers. A two-stage hyperinsulinemic-euglycemic clamp procedure, in conjunction with stable isotopically-labeled tracer infusions, demonstrated that resveratrol did not increase liver, skeletal muscle, or adipose tissue insulin sensitivity. Consistent with the absence of in vivo metabolic effects, resveratrol did not affect its putative molecular targets, including AMPK, Sirt1, Nampt, and Pgc-1a, in either skeletal muscle or adipose tissue. These findings demonstrate that resveratrol supplementation does not have metabolic effects in non-obese women.
GSE41505 CVMHuman Obesity 24 3 The aim of this study was to analyze gene response to a 10-week dietary intervention for weight loss in peripheral blood mononuclear cells of overweight/obese male children.
GSE41762 CVMHuman Diabetes 77 1 A gene co-expression network analysis has been conducted to identify T2D-associated gene modules. Donors 1-48 were used for the initial analysis and donors 49-80 for the replication and were normalized separately in this study
GSE41767 CVMHuman Diabetes 114 2 Diabetes and Arteriosclerosis progression are frequently observed in borderline Type 2 diabetes cases. Onset of complications (arteriosclerosis and renal damage) due to Type 2 diabetes is well documented; it is extremely important to prevent or delay their progression. Type 2 diabetes onset and progression has been controlled through dietary habits and exercise, although these remain insufficient. Chlorella ingestion improves blood glucose and cholesterol concentrations in mice and humans, although no reports have evaluated Chlorella effects in borderline diabetics. Therefore, we conducted a randomized, placebo-controlled trial for borderline diabetics using laboratory results and comprehensive gene analysis as outcomes. Chlorella ingestion suppressed resistin gene expression, suggesting that Chlorella may be useful for preventing diabetes onset and ameliorating arteriosclerosis.
GSE42432 CVMHuman Obesity 18 1 Polyphenolic compounds, such as resveratrol, have recently received widespread interest due to their ability to mimic effects of calorie restriction. The objective of the present study was to gain more insight into the effects of 30 days resveratrol supplementation on adipose tissue morphology and underlying processes. Nine healthy obese men were supplemented with placebo and 150mg/day resveratrol for 30 days, separated by a 4-week washout period. A postprandial abdominal subcutaneous adipose tissue biopsy was collected to assess adipose tissue morphology and gene expression using microarray analysis. Resveratrol significantly decreased adipocyte size, with a shift towards a reduction in the proportion of large and very large adipocytes and an increase in small adipocytes. Microarray analysis revealed downregulation of Wnt, Notch and BMP/TGF-ß signaling pathways and upregulation of pathways involved in cell cycle after resveratrol supplementation, suggesting enhanced adipogenesis. Furthermore, the lysosomal/phagosomal pathway and the transcription factor EB were upregulated, reflecting an alternative pathway of lipid breakdown by autophagy. These data suggest that adipose tissue is an important target tissue for the effects of resveratrol in humans, but further research is necessary to investigate whether it translates into an improved adipose tissue function.
GSE42902 CVMHuman Diabetes 16 2 Glucocorticoid excess is linked to central obesity, adipose tissue insulin resistance and type 2 diabetes mellitus. The aim of our study was to investigate the effects of dexamethasone on gene expression in human subcutaneous and omental adipose tissue, in order to identify potential novel mechanisms and biomarkers for glucocorticoid-induced insulin resistance in adipose tissue. Dexamethasone changed the expression of 527 genes in both subcutaneous and omental adipose tissue. FKBP5 and CNR1 were the most responsive genes in both depots (~7-fold increase). Dexamethasone increased FKBP5 gene and protein expression in a dose-dependent manner in both depots, but FKBP5 protein levels were 10-fold higher in omental than subcutaneous adipose tissue. FKBP5 gene expression in subcutaneous adipose tissue was positively correlated with serum insulin, HOMA-IR and subcutaneous adipocyte diameter, while fold change in gene expression by dexamethasone was negatively correlated with clinical markers of insulin resistance, i.e. HbA1c, BMI, HOMA-IR and serum insulin. Only one gene, SERTM1, clearly differed in response to dexamethasone between the two depots. Dexamethasone at high concentrations, influences gene expression in both subcutaneous and omental adipose tissue in a similar pattern and promotes gene expression of FKBP5, a gene that may be implicated in glucocorticoid-induced insulin resistance.
GSE43292 CVMHuman CVD 64 1 The aim of this study was to identify new biomarkers and to investigate pathways involved in the progression of human carotid atheroma.
GSE43471 CVMHuman Obesity 96 4 An ancillary study within a randomized trial of diet, exercise, or combined diet+exercise vs. control among overweight/obese postmenopausal women. Subcutaneous adipose-tissue biopsies were performed at baseline and after 6 months and changes in adipose-tissue gene expression were determined by microarray with an emphasis on pre-specified candidate pathways, as well as by unsupervised clustering. Analyses were conducted first by randomization group, and then by degree of weight change at 6-months in all women combined.
GSE43484 CVMHuman CKD 6 1 Patients with chronic kidney disease (CKD) have significantly increased morbidity and mortality resulting from infections and cardiovascular diseases. Since monocytes play an essential role in host immunity, this study was directed to explore the gene expression profile and to identify differences in activated pathways in monocytes relevant to the pathophysiology of atherosclerosis and increased susceptibility to infections. Monocytes from CKD patients (stages 4 and 5, eGFR <20 ml/min x 1.73 m2) and healthy donors were collected from peripheral blood. Microarray gene expression profile was done and data were interpreted by Genespring software and Panther tools website. Western blot was done to validate the pathway members. The results demonstrated that 487 and 258 genes were differentially up- and down regulated respectively in the patient group. Pathways involved in the inflammatory response were highly expressed and the Wnt/ß- catenin signaling pathway was the most significant pathway expressed in the patient group (P=0.02). Since this pathway has been attributed to a variety of inflammatory manifestations, the current finding may contribute to dysfunctional monocytes in CKD patients. To develop strategies to interfere with this pathway may improve host immunity and prevent cardiovascular complications in CKD patients.
GSE43488 CVMHuman Diabetes 356 1 To unravel genes and molecular pathways involved in the pathogenesis of type 1 diabetes (T1D), we performed genome-wide gene expression profiling of prospective venous blood samples from children developing T1D-associated autoantibodies or progressing towards clinical diagnosis.
GSE43685 CVMHuman Obesity 8 3 Maternal obesity during pregnancy leads to a pro-inflammatory milieu in the placenta. We conducted a global transcriptomic profiling in BeWo cells following palmitic acid (PA, 500 uM) and/or TNF-alpha (10 ng/ml) treatment for 24 h. Microarray analysis revealed that placental cytotrophoblasts increased expression of genes related to inflammation, stress response and immediate-early factors in response to plamitic acid, TNF-alpha or a combination of both. Our results suggest that fatty acids and inflammatory cytokines induce inflammation in placental cells via activation of JNK-Egr-1 signaling.
GSE44035 CVMHuman Diabetes 10 1 Expression profiling of cell cycle genes in human pancreatic islets with and without type 2 diabetes
GSE44461 CVMHuman CVD 6 1 Recent genome wide association studies have identified a number of genes that contribute to the risk for coronary heart disease. One such gene, TCF21, encodes a basic-helix-loop-helix transcription factor believed to serve a critical role in the development of epicardial progenitor cells that give rise to coronary artery smooth muscle cells (SMC) and cardiac fibroblasts. Using reporter gene and immunolocalization studies with mouse and human tissues we have found that vascular TCF21 expression in the adult is restricted primarily to adventitial cells associated with coronary arteries and also medial SMC in the proximal aorta of mouse. Genome wide RNA-Seq studies in human coronary artery SMC (HCASMC) with siRNA knockdown found a number of putative TCF21 downstream pathways identified by enrichment of terms related to CAD, including “vascular disease,” “disorder of artery,” and “occlusion of artery” as well as disease-related cellular functions including “cellular movement,” and “cellular growth and proliferation.” In vitro studies in HCASMC demonstrated that TCF21 expression promotes proliferation and migration and inhibits SMC lineage marker expression. Detailed in situ expression studies with reporter gene and lineage tracing revealed that vascular wall cells expressing Tcf21 before disease initiation migrate into vascular lesions of ApoE-/- and Ldlr-/- mice. While Tcf21 lineage traced cells are distributed throughout the early lesions, in mature lesions they contribute to the formation of a subcapsular layer of cells, and others become associated with the fibrous cap. The lineage traced fibrous cap cells activate expression of SMC markers and growth factor receptor genes. Taken together, these data suggest that TCF21 may have a role regulating the differentiation state of SMC precursor cells that migrate into vascular lesions and contribute to the fibrous cap and more broadly, in view of the association of this gene with human CAD, provide evidence that these processes may be a mechanism for CAD risk attributable to the vascular wall.
GSE45709 CVMHuman CKD 40 5 Background. Chronic renal failure is characterized by progressive renal scarring and accelerated cardiovascular disease. In animal models, this is thought to be due to non-dialyzable uremic toxins – small, protein-bound molecules normally secreted via Organic Anion Transporters (OATs) in the proximal renal tubule,rather than filtered at the glomerulus. The best studied of these is indoxyl sulfate (IS).\r\nMethods. We examined global gene expression responses in cultured normal human renal tubular cells incubated with control plasma (n=5) or pre- and post-dialysis uremic plasma (n=10).\r\nResults. GeneSpring analysis of microarrays revealed significantly altered expression of 2016 genes. The expression of 537 genes “normalized” in post-dialysis plasma, suggesting removal of “low molecular weight uremic toxins” by dialysis. The expression of the majority of dysregulated genes (1479) was not normalized in post-dialysis plasma. These likely represent the effects of substances not effectively removed by dialysis (“protein-bound uremic toxins”). Addition of indoxyl sulfateto control plasma simulated most effects (81.1%) of uremic plasma, while the addition of probenecid, an OAT inhibitor, to uremic plasma reversed most changes in gene expression. Analysis of molecular programs with the Gene Set Enrichment Analysis and the DAVID database revealed patterns common to indoxyl sulfate-treated control plasma, pre-dialysis, and post-dialysis uremic plasma. These included increased cell cycle, pro-inflammatory, and pro-fibrotic molecular programs, particularly genes in the TGF-ß pathway.\r\nConclusion: These findings provide insight into the role of non-dialyzable, protein-bound uremic toxins in the pathogenesis of renal scarring and uremic vasculopathy. The GSEA patterns confirm that inflammatory and fibrotic programs are active.
GSE45792 CVMHuman nomodel 298 0 Metabolic Syndrome (MetS) is a strong predictor for diabetes and cardiovascular disease and is defined by a constellation of phenotypes including increased and adverse body fat distribution, insulin resistance, abnormalities in lipids and lipoproteins, malfunctional cardiovascular performance, and abnormal levels of adipokines and cytokines. We assayed in a subset of our family cohort phentoyped for MetS phentoypes, the genome-wde transcript levels using the Illumina Human WG-6 v2 expression arrays.
GSE45980 CVMHuman nomodel 43 0 MicroRNAs (miRNAs) significantly contribute to chronic kidney disease (CKD) progression via regulating mRNA expression and abundance. However, their association with clinical outcome remains poorly understood. We performed large scale miRNA and mRNA expression profiling on cryo-cut renal biopsy sections from n=43 subjects. miRNAs differentiating stable and progressive cases were determined, and putative target mRNAs showing inversely correlated expression profiles were identified and further characterized. We found a downregulation of 7 miRNAs in the progressive phenotype, and an upregulation of 29 target mRNAs which are involved in inflammatory response, cell-cell-interaction, apoptosis, and intracellular signaling. Particularly a diminished expression of miR-206 in progressive disease correlated significantly with the upregulation of the target mRNAs CCL19, CXCL1, IFNAR2, NCK2, PTK2B, PTPRC, RASGRP1, and TNFRSF25, all participating in inflammatory pathways. Progressive cases also showed a decreased expression of miR-532-3p, and an increased expression of target transcripts MAP3K14, TNFRSF10B/TRAIL-R2, TRADD, and TRAF2, all being involved in apoptosis pathways. miR-206, miR-532-3p and all 12 mRNA targets correlated with the degree of histological damage.\r\nThe identified renal miRNA- and mRNA-profiles, and biological pathways may represent regulatory mechanisms, which are commonly present in various kinds of progressive chronic kidney disease.
GSE45986 CVMHuman nomodel 229 0 Metabolic Syndrome (MetS) is a strong predictor for diabetes and cardiovascular disease and is defined by a constellation of phenotypes including increased and adverse body fat distribution, insulin resistance, abnormalities in lipids and lipoproteins, malfunctional cardiovascular performance, and abnormal levels of adipokines and cytokines. We assayed in a subset of our family cohort phentoyped for MetS phentoypes, the genome-wde transcript levels using the Illumina Human WG-6 v3 expression arrays.
GSE46097 CVMHuman CVD 378 15 Intensive lifestyle modification is believed to mediate cardiovascular disease (CVD) risk through traditional pathways that affect endothelial function and progression of atherosclerosis; however, the extent, persistence, and clinical significance of molecular change during lifestyle modification are not well known. Our study reveals that gene expression signatures are significantly modulated by rigorous lifestyle behaviors and track with CVD risk profiles over time.
GSE46263 CVMHuman nomodel 66 0 Transcriptomic analysis of primary human umbilical vein endothelial cells (HUVEC). HUVEC were treated in vitro with CoCl2 to induce hypoxia, high glucose and high glucose plus hypoxia in different intervals (1, 3, 12 hours). Subsequently, the effect of metformin (anti-diabetic drug) on all conditions was studied to take advantage of transcriptomics to prospectively explore the mechanism of this drug to reduce the risk of cardiovascular diseases in type II diabetic patients.
GSE46300 CVMHuman Fatty-liver 18 1 With an estimated prevalence of about 30% in western countries non-alcoholic fatty liver disease (NAFLD) is a major public health issue [PMID: 18956290]. NAFLD is associated with the metabolic syndrome of insulin resistance, obesity, glucose intolerance. Although many studies are pointing to an induction of insulin resistance by NAFLD causality between both phenotypes is not fully clarified. Furthermore, mechanisms leading to strongly differing progression of NAFLD have to be elucidated which range from mild steatosis up to severe steatohepatitis. Steatohepatitis might even result in liver cirrhosis and hepatocellular carcinoma. Additional complexity is introduced into the understanding of the disease by recent studies providing evidence for a direct development of carcinoma from steatosis without the formerly assumed intermediary phase of cirrhosis. Here, we investigate liver samples from patients with varying severities of steatosis in an integrative approach employing transcriptomics, serum biomarker profling, metabolomics data and systems biology models.
GSE46699 CVMHuman Obesity 130 4 Both cigarette smoking and obesity have been implicated in increased risk of clear cell renal cell carcinoma (ccRCC); however, there are limited data regarding the molecular mechanisms that underlie these associations. We used a multi-stage design to identify and validate specific molecular targets that are associated with smoking or obesity-related ccRCC.
GSE47183 CVMHuman CKD 122 10 To identify genes with cell-lineage-specific expression not accessible by experimental micro-dissection, we developed a genome-scale iterative method, in-silico nano-dissection, which leverages high-throughput functional-genomics data from tissue homogenates using a machine-learning framework.\r\nThis study applied nano-dissection to chronic kidney disease and identified transcripts specific to podocytes, key cells in the glomerular filter responsible for hereditary proteinuric syndromes and acquired CKD. In-silico prediction accuracy exceeded predictions derived from fluorescence-tagged-murine podocytes, identified genes recently implicated in hereditary glomerular disease and predicted genes significantly correlated with kidney function. The nano-dissection method is broadly applicable to define lineage specificity in many functional and disease contexts.
GSE47184 CVMHuman CKD 107 13 To identify genes with cell-lineage-specific expression not accessible by experimental micro-dissection, we developed a genome-scale iterative method, in-silico nano-dissection, which leverages high-throughput functional-genomics data from tissue homogenates using a machine-learning framework.\r\nThis study applied nano-dissection to chronic kidney disease and identified transcripts specific to podocytes, key cells in the glomerular filter responsible for hereditary proteinuric syndromes and acquired CKD. In-silico prediction accuracy exceeded predictions derived from fluorescence-tagged-murine podocytes, identified genes recently implicated in hereditary glomerular disease and predicted genes significantly correlated with kidney function. The nano-dissection method is broadly applicable to define lineage specificity in many functional and disease contexts.
GSE47185 CVMHuman BI-requested 229 20 This SuperSeries is composed of the SubSeries listed below.
GSE474 CVMHuman Obesity 24 1 It has been found that fat oxidation is reduced in the skeletal muscle of obese humans. This study aims to identify the mRNA of proteins involved in fat oxidation that may be reduced in obese and morbidly obese individuals. Information gathered will help in understanding how obesity contributes to cardiovascular disease via insulin resistance.
GSE47727 CVMHuman nomodel 122 0 Samples were collected from 'control participants' of the Heart and Vascular Health (HVH) study that constitutes a group of population based case control studies of myocardial infarction (MI), stroke, venous thromboembolism (VTE), and atrial fibrillation (AF) conducted among 30-79 year old members of Group Health, a large integrated health care organization in Washington State.
GSE47728 CVMHuman nomodel 228 0 Samples were collected from 'control participants' of the Heart and Vascular Health (HVH) study that constitutes a group of population based case control studies of myocardial infarction (MI), stroke, venous thromboembolism (VTE), and atrial fibrillation (AF) conducted among 30-79 year old members of Group Health, a large integrated health care organization in Washington State.
GSE48101 CVMHuman Diabetes 9 1 Access to an unlimited number of human pancreatic beta cells represents a major challenge in the field of diabetes to better dissect human beta cell functions and to make significant progress in drug discovery and cell replacement therapies. We previously reported the generation of the EndoC-bH1 human beta cell line that was generated by targeted oncogenesis in human fetal pancreases followed by in vivo cell differentiation in mice. Such cell line displayed many functional properties of adult beta cells. Here we devised a novel strategy to generate conditionally immortalized human beta cell lines based on CRE-mediated excision of immortalizing transgenes. The resulting EndoC-bH2 cell line can be massively amplified in vitro. Transgenes are next efficiently excised upon CRE expression leading to cell proliferation arrest and strong enhancement of beta cell specific features such as insulin expression, content and secretion. Excised EndoC-bH2 cells are close to authentic human beta cells and represent a unique tool to further study beta cell function and to understand why adult human beta cells are refractory to proliferation and how to achieve drug-dependent mobilization towards beta cell expansion.
GSE48278 CVMHuman Diabetes 114 16 Skeletal muscle adapts to exercise training of various modes, intensities and durations with a programmed gene expression response. This study dissects the independent and combined effects of exercise mode, intensity and duration to identify which exercise has the most positive effects on skeletal muscle health. Full details on exercise groups can be found in: Kraus et al Med Sci Sports Exerc. 2001 Oct;33(10):1774-84 and Bateman et al Am J Cardiol. 2011 Sep 15;108(6):838-44.
GSE48452 CVMHuman fatty liver 73 3 Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in industrialized countries. Liver samples from morbidly obese patients (N=45) with all stages of NAFLD and controls (N=18) were analysed by array-based DNA methylation and mRNA expression profiling. NAFLD-specific expression and methylation differences were seen for nine genes coding for key enzymes in intermediate metabolism (including PC, ACLY, PLCG1) and insulin/insulin-like signalling (including IGF1, IGFBP2, PRKCE) and replicated by bisulfite pyrosequening (independent N=39). Transcription factor binding sites at NAFLD-specific CpG sites were >1000-fold enriched for ZNF274, PGC1A and SREBP2. Intra-individual comparison of liver biopsies before and after bariatric surgery showed NAFLD-associated methylation changes to be partially reversible. Post-bariatric and NAFLD-specific methylation signatures were clearly distinct both in gene-ontology and transcription factor binding site analyses, with >400-fold enrichment of NRF1, HSF1 and ESRRA sites. Our findings provide one of the first examples of treatment-induced epigenetic organ remodelling in humans.
GSE48521 CVMHuman Obesity 16 2 To investigate fetal gene expression in obese compared to lean women in the second trimester, by performing global gene expression analysis of amniotic fluid (AF) cell-free RNA\r\nAnalysis of paired data from obese cases and lean controls revealed differential expression of 205 genes. Functional analysis of differentially expressed genes suggested down-regulation of apoptosis in fetuses of obese women, particularly within nervous system pathways involving the cerebral cortex, and activation of pro-estrogenic, pro-inflammatory transcriptional regulators.
GSE48964 CVMHuman Obesity 6 1 The adipose tissue is an endocrine regulator and a risk factor for atherosclerosis and cardiovascular disease when by excessive accumulation induces obesity. Although the adipose tissue is also a reservoir for stem cells (ASC) their function and “stemcellness” has been questioned. Our aim was to investigate the mechanisms by which obesity affects subcutaneous white adipose tissue (WAT) stem cells.\r\nWe used microarrays to analyze differences in transcriptomic profiles between the adipose stem cells from morbidly obese and non-obese individuals.
GSE49541 CVMHuman Fatty-liver 72 1 Nonalcoholic fatty liver disease represents a spectrum of pathology that ranges from benign steatosis to potentially-progressive steatohepatitis and affects more than 30% of US adults. Advanced NAFLD is associated with increased morbidity and mortality from cirrhosis, primary liver cancer, cardiovascular disease and extrahepatic cancers.\r\nAccurate identification of patients at risk for advanced NAFLD is challenging. The aims of this study were to define the liver gene expression patterns that distinguish mild from advanced NAFLD and to develop a gene expression profile associated with advanced NAFLD.
GSE49925 CVMHuman nomodel 338 0 Whole peripheral blood samples collected into Paxgene tubes from 338 adult participants in the Emory University Cardiovascular Biobank, in Midtown Atlanta. The sample is of mixed cardiovascular function diversity, and is part of a survey of the impact of status of cardiovascular disease on gene expression and clinical attributes. Sample annotations only include gender and proofed ethnicity for purposes of IRB, as well as technical features of the study (plate, phase of study, and RNA quality RIN score).
GSE50244 CVMHuman Diabetes 89 2 Here we harnessed the potential of RNA sequencing in 89 human pancreatic islet donors to identify genes and exons regulated in this relevant tissue for T2D.
GSE50397 CVMHuman Diabetes 89 2 Here we harnessed the potential of expression arrays in 89 human pancreatic islet donors (different levels of blood glucose (HbA1c)) to identify genes regulated in this relevant tissue for type 2 diabetes (T2D).
GSE51058 CVMHuman Diabetes 36 1 To identify genes with expression levels that are associated with T1D progression from AbP (islet autoantibody positive), global gene expression changes were analyzed in AbP subjects with different T1D progression rate.
GSE5109 CVMHuman Obesity 6 1 Obesity results from a chronic imbalance between energy intake and energy expenditure, with excess calories stored as fat. As such, weight loss has long been considered as a primary goal of treatment for obesity. A surgical treatment of severe obesity such as gastric bypass provides the most dramatic reductions in body weight, and a well-known effect of weight loss is an improvement in insulin sensitivity. However, the molecular mechanism underlying this association remains unclear. Thus, we profiled skeletal muscle of morbidly obese patients before and after gastric bypass surgery. Results from this project will provide global patterns of gene expression with weight loss, which help to understand the pathogenesis of obesity at the molecular level.
GSE52376 CVMHuman Diabetes 23 2 By restraining T cell activation and promoting regulatory T cell (Treg) expansion, myeloid-derived suppressor cells (MDSC) and tolerogenic dendritic cells (DC) (tDC) can control self-reactive and anti-graft effector T cells in autoimmunity and transplantation. Their therapeutic use and characterization, however, is limited by their scarce availability in the peripheral blood of tumor-free donors. In the present study we describe and characterize a novel population of myeloid suppressor cells, named fibrocytic MDSC (f-MDSC), that are differentiated from umbilical cord blood (UCB) precursors by a 4 day culture with FDA approved cytokines (rh-GM-CSF and rh-G-CSF). This MDSC subset, characterized by the expression of MDSC-, DC-, and fybrocyte-s associated markers, promotes Treg regulatory cells expansion and promote normoglycemia in a xenogeneic model of Type 1 Diabetes (T1D). In order to exert their pro-tolerogenic function, fibrocytic MDSC require direct contact with activated T cells, which leads to the induction and secretion of indoleamine 2,3 deoxygenase (IDO). This new myeloid subset may represent an important tool for the in vitro and in vivo production of Treg for the treatment of autoimmune diseases, and either prevention or control of allograft rejection.
GSE53232 CVMHuman Obesity 128 6 Early perturbations in vascular health can be detected by imposing subjects to a high fat (HF) challenge and measure response capacity. Subtle responses can be determined by assessment of whole-genome transcriptional changes. We aimed to magnify differences in health by comparing gene-expression changes in peripheral blood mononuclear cells (PBMCs) towards a high MUFA or SFA challenge between subjects with different cardiovascular disease risk profiles and to identify fatty-acid specific gene-expression pathways.\r\nMETHODS AND RESULTS: In a cross-over study, 17 lean and 15 obese men (50-70y) received two 95g fat shakes, high in SFAs or MUFAs. PBMC gene-expression profiles were assessed fasted and 4h postprandially. Comparisons were made between groups and shakes. During fasting, 294 genes were significantly different expressed between lean and obese. The challenge increased differences to 607 genes after SFA and 2516 genes after MUFA. In both groups, SFA decreased expression of cholesterol biosynthesis and uptake genes and increased cholesterol efflux genes. MUFA increased inflammatory genes and PPARa targets involved in ß-oxidation.\r\nCONCLUSION: Based upon gene-expression changes, we conclude that a HF challenge magnifies differences in health, especially after MUFA. Our findings also demonstrate how SFAs and MUFAs exert distinct effects on lipid handling pathways in immune cells.
GSE53291 CVMHuman Obesity 16 2 Previously, we have examined the effect of maternal dietary n-3 LCPUFA supplementation during pregnancy to reduce offspring obesity risk. Considering the involvement of the placenta in fetal programming, we here analyzed the sexually dimorphic potential of placental gene expression, its response to the n-3 LCPUFA intervention and their correlation to offspring obesity risk.\r\nThe placenta is implicated to play a key role in mediating fetal /metabolic programming of the offspring in utero. For human and mouse models, it has been reported that male and female fetuses differentially respond to in utero environmental stimuli. Moreover, sexual dimorphism is also known for placental gene expression, LCPUFA metabolism and adipose tissue distribution. Therefore, we explored whether the maternal n-3 LCPUFA intervention during pregnancy has a sex-specific impact on the term placental transcriptome in a defined subpopulation of the INFAT (impact of nutritional fatty acids during pregnancy and lactation on early human adipose tissue development) study. In addition, we assessed the relationships between sex-specific placental gene expression and sex steroids levels, and expression changes of specific genes and offspring obesity risk. Overall, human term placentas show sexually dimorphic gene expression and respond sex-specifically to dietary maternal n-3 LCPUFA intervention during pregnancy with more pronounced effects on gene expression and estradiol-17ß/testosterone ratio in female than male placentas.
GSE53376 CVMHuman Obesity 32 1 Molecular mechanisms associated with pathophysiological variations in adipose tissue (AT) are not fully recognized. The main aim of this study was to identify novel candidate genes and miRNAs that may contribute to the pathophysiology of hyperplastic AT. Therefore, wide gene and microRNA (miRNA) expression patterns were assessed in subcutaneous AT of 16 morbidly obese women before and after surgery-induced weight loss. Validation of microarray data was performed by quantitative real-time PCR both longitudinally (n=25 paired samples) and cross-sectionally (25 obese vs. 26 age-matched lean women). Analyses in macrophages and differentiated human adipocytes were also performed to try to comprehend the associations found in AT. 5,018 different probe sets identified significant variations in gene expression after treatment (adjusted p-value<0.05). A set of 16 miRNAs also showed significant modifications. Functional analysis revealed changes in genes and miRNAs associated with cell cycle, development and proliferation, lipid metabolism, and the inflammatory response. Canonical affected pathways included TREM1, PI3K, and EIF2 signaling, hepatic stellate cell activation, and mitochondrial function. Increased expression of SLC27A2, ELOVL6, FASN, GYS2, LGALS12, PKP2, ACLY, and miR-575, as well as decreased FOS, EGFL6, PRG4, AQP9, DUSP1, RGS1, EGR1, SPP1, LYZ, miR-130b, miR-221, and miR-155, were further validated. The clustering of similar expression patterns for gene products with related functions revealed molecular footprints, some of them described for the first time, which elucidate changes in biological processes after the surgery-induced weight loss.
GSE53454 CVMHuman Diabetes 90 18 In the context of T1 Diabetes, pro-inflammatory cytokines IL-1ß and IFN-? are known to contribute to ß-cell apoptosis;\r\nThe measurement of mRNA expression following ß-cell exposure to these cytokines gives a picture of the changes in gene expression characterizing the path to ß-cell dysfunction and death.
GSE53949 CVMHuman Diabetes 10 1 Pancreatic beta-cell dysfunction and death are central in the pathogenesis of type 2 diabetes. Saturated fatty acids cause beta-cell failure and contribute to diabetes development in genetically predisposed individuals. Here we used RNA-sequencing to map transcripts expressed in five palmitate-treated human islet preparations, observing 1,325 modified genes. Palmitate induced fatty acid metabolism and endoplasmic reticulum (ER) stress. Functional studies identified novel mediators of adaptive ER stress signaling. Palmitate modified genes regulating ubiquitin and proteasome function, autophagy and apoptosis. Inhibition of autophagic flux and lysosome function contributed to lipotoxicity. Palmitate inhibited transcription factors controlling beta-cell phenotype including PAX4 and GATA6. 59 type 2 diabetes candidate genes were expressed in human islets, and 11 were modified by palmitate. Palmitate modified expression of 17 splicing factors and shifted alternative splicing of 3,525 transcripts. Ingenuity Pathway Analysis of modified transcripts and genes confirmed that top changed functions related to cell death. DAVID analysis of transcription binding sites in palmitate-modified transcripts revealed a role for PAX4, GATA and the ER stress response regulators XBP1 and ATF6. This human islet transcriptome study identified novel mechanisms of palmitate-induced beta-cell dysfunction and death. The data point to crosstalk between metabolic stress and candidate genes at the beta-cell level.
GSE5406 CVMHuman CVD 210 2 Left ventricular myocardium was snap-frozen at time of cardiac transplantation from patients with advanced idiopathic or ischemic cardiomyopathy, or at time of harvest from unused donor heart that serve as a nonfailing control. No subjects received mechanical support devices.
GSE54279 CVMHuman Diabetes 128 3 Pancreatic islets are central in type 2-diabetes development, which coincides with increased activity of innate immunity. Intriguingly, human pancreatic islets express many complement genes. The most highly expressed gene was the complement inhibitor CD59 that is GPI anchored to the cell membrane, which unexpectedly was found in high amounts intracellularly in beta cells. Silencing of CD59 strongly suppressed insulin secretion. Importantly, this suppression was unrelated to established CD59 functions, but rather depletion of intracellular CD59. Imaging experiments identified a distal site of inhibition in the exocytotic pathway, but prior to emptying of the insulin granules. Proximity Ligation Assays pin-pointed the mechanism to impaired turnover of exocytosis-regulating SNARE-proteins and CD59 was detected in complex with VAMP2 and syntaxin. CD59 was downregulated by 24-h glucose incubations in human islets, rat cell lines and in islets from three rodent diabetes models.
GSE54350 CVMHuman Obesity 12 1 Identification of the inflammatory signature in visceral adipose tissue CD14+ cells (adipose tissue macrophage)\r\nTotal RNA obtained from CD14+ cells (Immunoselcted cells from stromal adipose tissue cells)
GSE54606 CVMHuman Obesity 22 10 Analysis of A549 gene expression (mRNA) after 24 hour exposure to ten different doses of obese visceral adipocyte exosomes. The hypothesis is that obese visceral adipocyte exosomes genetically regulate genes in the TGFß and Wnt-ßcatenin pathways.
GSE55008 CVMHuman Obesity 6 1 Purpose: To profile the transcriptomes of omental adipose tissues from obese and lean humans.\r\nMethods: Omental adipose tissues from obese and lean patients were subjected to RNA-Seq.\r\nResults: Differential expression analysis identified 206 dysregulated genes (p-value < 0.05 by moderated t-test and fold change = 2 in obesity) that are known to be involved in a multitude of functions, including response to stress, inflammatory response and leukocyte adhesion. Differential splicing analysis uncovered the possible role of TLR4 RNA splicing in obesity. Our findings suggest that, as a person experiences weight gain/obesity, the adipose splicing pattern of TLR4 transcripts changes in favor of activation of TLR4 signaling, which in turn may contribute to the progression of obesity-related inflammation and complications.\r\nConclusion: This study provides a look into the transcriptome of disease-state adipose tissue in obesity, and demonstrates the potential importance of aberrant RNA splicing and expression in obesity-associated immune dysregulation.
GSE55098 CVMHuman Diabetes 22 1 Type 1 diabetes mellitus (T1D) is a common autoimmune disease mediated by autoimmune attack against pancreatic b cells.Dys-regualtion of the component of peripheral blood mononuclear cells (PBMCs), including T-cells and B-cells, and smaller amounts of NK cells and dendritic cells, have all been implicated in this process\r\nThis study sought to identify T1D associated differently expressed genes in the peripheral blood mononuclear cell (PBMC).
GSE55100 CVMHuman Diabetes 22 1 This SuperSeries is composed of the SubSeries listed below.
GSE55200 CVMHuman Obesity 23 3 Obesity is a heterogeneous conditions comprising obese individuals with metabolic disorders (termed metabolically unhealthy obese; MUO) and obese individuals who are metabolically healthy (termed metabolically healthy obese; MHO).\r\nWe used microarrays to examine differences in subcutaneous adipose tissue gene expression from lean healthy (LH), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO) individuals.
GSE55205 CVMHuman Obesity 23 2 The aim of study was to investigate correlation bewteen peripheral blood mononuclear cell (PBMC) transcriptome profiles and plasma lipid profiles of Korean adult with varying BMI. In Korean, BMI cut-off points are 18.5~22.9 kg/m2 (normal range), = 23 kg/m2 (overweight), = 25 kg/m2 (obese), = 30 kg/m2 (severely obese). Thus, the obese group was subdivided into mildly obese (BMI 25~27 kg/m2, OA) and highly obese (BMI 27~30 kg/m2, OB). This study indicates that lipid, glucose and inflammation metabolism-related gene expressions were altered according to cahnge of varing phenotype biomarkers such as BMI, plasma total-C, TG, FFA and HDL-C. Thus, blood biomarkers and PBMC gene expression profiles identified in this study may be useful as indicative biomarkers for obese susceptibility in Korean adult as well as response to various intervention for treating obesity.
GSE55650 CVMHuman Diabetes 23 2 Skeletal muscle is the key site of peripheral insulin resistance in type 2 diabetes. Insulin-stimulated glucose uptake is decreased in differentiated diabetic myotubes in keeping with a retained genetic/epigenetic defect of insulin action.\r\nMicroarray analysis was used to investigate differences in gene expression with differentiation in diabetic cultures compared to controls.
GSE56716 CVMHuman Obesity 112 4 In a randomized controlled dietary intervention study we compared an isocaloric Healthy Nordic diet with the average Nordic diet for influence on abdominal subcutaneous adipose tisse gene expression. We studied obese adults with features of the metabolic syndrom, n=56. There was no significant difference in age, BMI, or gene expression between the groups before the intervention. The intervention lasted for 18-24 weeks.\r\nGene expression was analyzed using linear mixed-effects models including specific genes as dependent variable, subject identifier as a random effect, and body weight, age, gender, study centre (i.e. also study duration), study group, time-point and study group * time-point interaction as covariates. 128 genes were significantly different regulated by the two diets with a FDR of 24%. TThese genes were overrepresented in pathways related to immune response. I conclusion, a Healthy Nordic diet reduces inflammatory gene expression in abdominal subcutaneous adipose tissue. This could contribute to beneficial influences on lipid metabolism and cardiovascular disease.
GSE57691 CVMHuman CVD 68 3 The aim of this study was to assess the relative gene expression in human AAA and AOD.
GSE57802 CVMHuman Obesity 99 2 The 600kb BP4-BP5 16p11.2 CNV (copy number variant) is associated with neuroanatomical, neurocognitive and metabolic disorders. These recurrent rearrangements are associated with reciprocal phenotypes such as obesity and underweight, macro- and microcephaly, as well as autism spectrum disorder (ASD) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal CNVs in 16p11.2.\r\nThe genome-wide transcript perturbations correlated with clinical endophenotypes of the CNV and were enriched for genes associated with ASD. We uncovered a significant correlation between copy number changes and expression levels of genes mutated in ciliopathies.
GSE57896 CVMHuman Diabetes 30 8 The rising incidence of obesity and related disorders such as diabetes and heart disease has focused considerable attention on the discovery of novel therapeutics. One promising approach has been to increase the number or activity of brown-like adipocytes in white adipose depots, as this has been shown to prevent diet-induced obesity and reduce the incidence and severity of type 2 diabetes. Thus, the conversion of fat-storing cells into metabolically active thermogenic cells has become an appealing therapeutic strategy to combat obesity. Here, we report a screening platform for the identification of small molecules capable of promoting a white-to-brown metabolic conversion in human adipocytes. We identified two inhibitors of Janus Kinase (JAK) activity with no precedent in adipose tissue biology that permanently confer brown-like metabolic activity to white adipocytes. Importantly, these metabolically converted adipocytes exhibit elevated UCP1 expression and increased mitochondrial activity. We further found that repression of interferon signalling and activation of hedgehog signalling in JAK-inactivated adipocytes contributes to the metabolic conversion observed in these cells. Our findings highlight a novel role for the JAK/STAT pathway in the control of adipocyte function and establish a platform to identify compounds for the treatment of obesity.
GSE57928 CVMHuman Diabetes 9 2 This SuperSeries is composed of the SubSeries listed below.
GSE58150 CVMHuman CVD 16 1 Peripheral blood RNA-Seq from human coronary artery calcification cases and controls; Coronary artery calcification (CAC) is a heritable and definitive morphologic marker of atherosclerosis that strongly predicts risk for future cardiovascular events. To search for genes involved in CAC, we used an integrative transcriptomic, genomic, and protein expression strategy using next-generation DNA sequencing in the discovery phase with follow-up studies using traditional molecular biology and histopathology techniques.
GSE58516 CVMHuman Obesity 15 2 Bisphenol A (BPA) is a xenobiotic endocrine disrupting chemical. In vitro and in vivo studies indicated that BPA alters endocrine-metabolic pathways in adipose tissue increasing the risk of developing metabolic disorders. BPA effects on human adipocytes, specifically in children, are poorly investigated. To investigate in childhood the effect of exposure to BPA on metabolic disorders we analyzed in vitro the effects of environmentally relevant doses of BPA on gene expression of mature human adipocytes from pre-pubertal lean patients and on related physiological outcomes. Adipocytes from children were treated in vitro with BPA and gene expression was evaluated by qRT-PCR. Genome wide analyses were performed using GeneChip® Human Gene 1.0 ST array. Lipid content in adipocytes was estimated by ORO staining and Triglyceride Quantification Kit. Secreted IL-1ß, in adipocytes culture medium, and insulin, in PANC-1 culture medium, were performed using ELISA assays. BPA was found to promote up-regulation of ERa and ERR?, and down-regulation of GPR30 expression modulating estrogen signaling and following a non-linear dose-response. Microarray data analysis demonstrated that BPA increases the gene expression of pro-inflammatory cytokines and lipid metabolism-related FABP4 and CD36 in adipocytes. PCSK1 resulted the most interesting gene being down-regulated by BPA thus impairing insulin production in pancreas. BPA promotes inflammation and lipid metabolism dysregulation in adipocytes from lean children. Moreover, PCSK1 can be a key gene in BPA action modulating insulin production. Exposure to BPA in childhood may be an important risk factor in developing obesity and metabolic disorders.
GSE58979 CVMHuman fatty liver 53 6 Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of liver disease affecting 20-30% of the population in developed countries. NAFLD is strongly associated with abdominal obesity and is recognized as the hepatic manifestation of the metabolic syndrome. In a subgroup of patients with NAFLD inflammation and fibrosis develops, this so-called Non-Alcoholic Steatohepatitis (NASH) may progress to cirrhosis and hepatocellular carcinoma. A multi-hit hypothesis has been proposed in which during the first “hit” fat accumulation occurs in hepatocytes from excessive delivery of fatty acids from adipose tissue, in addition there is an imbalance in lipid synthesis and export. However, the reason why fat accumulation is subsequently followed by inflammation and fibrosis in some patients is poorly understood. We studied the role of inflammatory processes in visceral and subcutaneous fat at the transcriptional level using microarray in bariatric patients from whom the liver histology was available.
GSE59045 CVMHuman fatty liver 15 2 Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of liver disease affecting 20-30% of the population in developed countries. NAFLD is strongly associated with abdominal obesity and is recognized as the hepatic manifestation of the metabolic syndrome. In a subgroup of patients with NAFLD inflammation and fibrosis develops, this so-called Non-Alcoholic Steatohepatitis (NASH) may progress to cirrhosis and hepatocellular carcinoma. A multi-hit hypothesis has been proposed in which during the first “hit” fat accumulation occurs in hepatocytes from excessive delivery of fatty acids from adipose tissue, in addition there is an imbalance in lipid synthesis and export. However, the reason why fat accumulation is subsequently followed by inflammation and fibrosis in some patients is poorly understood. We studied the role of gene expression at the transcriptional level using microarray in bariatric patients from whom the liver histology was available.
GSE59128 CVMHuman CVD 80 5 Background: Basal cells within the human airway epithelium constitute the stem/progenitor cells for other epithelial cell types. Basal cells respond to mucosal injury and damage to the airway mucosa in an ordered sequence of spreading, migration, proliferation and phenotype shifting (differentiation) to other needed cell types. However, dynamic gene transcription in the early events of injury and repair has not been examined in these cells. Methodology and findings: Airway epithelial cells were obtained from donated lungs and grown in submersion culture on pliable membranes to obtain a pure population of basal cells. Microarrays were used to assess the transcriptome of basal cells 8 and 24 hr after mechanical injury (MI), or to cyclic stretch (CS) in a Flexcell system (0.5 Hz, 20% distension), or both treatments. We identified 121 signature genes with > 2-fold higher differential expression (DE) 8 hr after MI; expression of nearly all of these genes returned to baseline at 24 hr after injury. In cells subjected to CS, little change in DE was noted at 8 hr, whereas at 24 hr a CS signature of 1430 DE genes were identified. The MI signature was characterized by genes encoding growth factor receptors related to the EGF pathway, IL-6, IL-8 and IL-33, extracellular matrix components, and NF-kB and p38-MAPK signaling pathways, whereas the CS signature was characterized by a broad range of genes that did not identify specific signaling pathways. Combined MI and CS at 8 hr elicited DE of down-regulated genes not seen with either stimulus alone, and at 24 hr elicited DE that was similar to that seen with CS alone. Conclusion and significance: The human airway basal epithelial cell transcription signature in the first hours after MI, after CS, and after both stimuli identifies unique differentially expressed genes and pathways that may be important in the early molecular response and biology to airway injury.
GSE59867 CVMHuman CVD 436 7 Heart failure (HF) is the most common cause of morbidity and mortality in the developed countries, especially considering the present demographic tendencies in those populations.\r\nWe identified biologically relevant transcripts that are significantly altered in the early phase of myocardial infarction (MI) and are associated with the development of post-myocardial infarction HF.
GSE60436 CVMHuman Diabetes 9 2 Proliferative diabetic retinopathy (PDR) is a vision-threatening disorder characterized by the formation of cicatricial fibrovascular membranes leading to traction retinal detachment. Despite the recent advance in the treatment of PDR such as vitreoretinal surgery with use of anti-vascular endothelial growth factor (VEGF) drug as an adjunct, it still remains vision-threatening disease.\r\nIn order to identify genes associated with the pathogenesis of PDR, we performed gene expression analyses in fibrovascular membrane in patients with PDR using DNA microarray technology.
GSE60803 CVMHuman Diabetes 12 3 In vitro expansion of adult human islet ß cells is an attractive solution for the shortage of tissue for cell replacement therapy of type 1 diabetes. Using a lineage tracing approach, we have demonstrated that ß-cell-derived (BCD) cells rapidly dedifferentiate in culture and can proliferate for up to 16 population doublings. Dedifferentiation is associated with changes resembling epithelial-mesenchymal transition (EMT). The WNT pathway has been shown to induce EMT and plays key roles in regulating replication and differentiation in many cell types. Here we show that BCD cell dedifferentiation is associated with ß-catenin translocation into the nucleus and activation of the WNT pathway. Inhibition of ß-catenin expression in expanded BCD cells using short hairpin RNA resulted in growth arrest, mesenchymal-epithelial transition, and redifferentiation, as judged by activation of ß-cell gene expression. Furthermore, inhibition of ß-catenin expression synergized with redifferentiation induced by a combination of soluble factors, as judged by an increase in the number of C-peptide-positive cells. Simultaneous inhibition of the WNT and NOTCH pathways also resulted in a synergistic effect on redifferentiation. These findings, which were reproducible in cells derived from multiple human donors, suggest that inhibition of the WNT pathway may contribute to a therapeutically applicable way for generation of functional insulin-producing cells following ex-vivo expansion.
GSE60860 CVMHuman CKD 29 5 MicroRNAs (miRNAs) contribute to chronic kidney disease progression via negatively regulating mRNA abundance. However, their association with clinical outcome remains poorly understood. We performed large-scale miRNA and mRNA expression profiling on cryo-cut renal biopsy sections from a discovery (n=43) and a validation (n=29) cohort. In the discovery cohort (GEO Series accession number GSE45980), miRNAs differentiating stable and progressive cases were determined, and putative target mRNAs showing inversely correlated expression profiles were identified. We found a downregulation of 7 miRNAs in the progressive phenotype, and an upregulation of 29 target mRNAs that are involved in inflammatory response, cell-cell-interaction, apoptosis, and intracellular signaling. Reduced expression of miR-206 in progressive disease correlated with the upregulation of the target mRNAs CCL19, CXCL1, IFNAR2, NCK2, PTK2B, PTPRC, RASGRP1, and TNFRSF25, all participating in inflammatory pathways. Progressive cases also showed a lower expression of miR-532-3p and an increased expression of cognate target transcripts MAP3K14, TNFRSF10B/TRAIL-R2, TRADD, and TRAF2, all being involved in apoptosis pathways. In the independent validation cohort (this set of arrays), we confirmed the decreased expression of miR-206 and miR-532-3p, and the inverse correlation of these miRNAs with the expression of 9 of the 12 target genes. The levels of the identified miRNAs and the target mRNAs correlated to histological damage indices. These results suggest the involvement of specific miRNAs and mRNAs in biological pathways associated with the progression of chronic kidney disease.
GSE60937 CVMHuman CKD 9 2 Hyperphosphatemia is an independent risk factor for cardiovascular mortality in chronic kidney disease. High inorganic phosphorus can induce endothelial cell apoptosis, but the exact mechanism is not fully understood. This study addresses this knowledge gap.Microarray analysis was used to identify differentially expressed gene profiles in human umbilical vein endothelial cells (HUVECs) in high phosphate (3.0 mM) normal phosphate (1.0 mM) medium and low phosphate( 0.5mM).
GSE61260 CVMHuman Obesity 134 5 N=134 human liver samples from morbidly obese patients and healthy controls were analysed by array-based mRNA expression profiling. Liver messenger RNA expression datasets from the German patients were generated on the HuGene 1.1 ST gene array The purpose of the study was to correlate these gene expression data with body mass index and with an epigenetic measure of age acceleration based on DNA methylation data.
GSE62199 CVMHuman CVD 201 2 Food composition of diets strongly determines the risk of experiencing inflammation related metabolic or cardiovascular disease. We aimed to determine the extent of inheritance of inflammatory responses to isocaloric changes in food composition as a prerequisite of personalized dietary recommendations in human twins.
GSE62547 CVMHuman Fatty-liver 6 1 Human skin-derived precursor cells (hSKP) are a post natal stem cell population isolated from the dermis. These cells acquire hepatic characteristics upon differentiation with hepatogenic factors. Differentiated hSKP show characteristics of hepatocyte precursor cells and respond to hepatotoxic compounds in a comparable way as human hepatocyte cultures.\r\nWe used microarray analyses to evaluate the modulation of gene expression due to exposure to a steatosis-inducing compound.
GSE62646 CVMHuman CVD 98 5 Despite a substantial progress in diagnosis and therapy, acute myocardial infarction (MI) is a major cause of mortality in the general population. A novel insight into the pathophysiology of myocardial infarction obtained by studying gene expression should help to discover novel biomarkers of MI and to suggest novel strategies of therapy. The aim of our study was to establish gene expression patterns in leukocytes from acute myocardial infarction patients.\r\nST-segment elevation myocardial infarction alters expression of several groups of genes. On admission, several genes and pathways that could be directly or indirectly linked with lipid/glucose metabolism, platelet function and atherosclerotic plaque stability were affected (signaling of PPAR, IL-10, IL-6). Analysis at discharge highlighted specific immune response (upregulation of immunoglobulins). Highly significant and substantial upregulation of SOCS3 and FAM20 genes expression in the first 4-6 days of myocardial infarction in all patients is the most robust observation of our work
GSE6280 CVMHuman CKD 40 16 End stage renal disease (ESRD) is associated with hyperplastic-cystic remodelling of the kidneys (ARCD) and increased rate of kidney tumours. Using the Affymetrix oligoarray, we have established the gene expression signature of ESRD/ARCD kidneys and compared to those of normal kidneys and of distinct types of renal tumours.
GSE62832 CVMHuman Diabetes 36 4 Obesity is associated with insulin resistance and increased intrahepatic triglyceride (IHTG) content, which are key risk factors for diabetes and cardiovascular disease. However, a subset of obese people does not develop these metabolic complications. We tested the hypothesis that MNO, but not MAO, people are protected from the adverse metabolic effects of weight gain. To this end, global transcriptional profile in adipose tissue before and after weight gain was evaluated by microarray analyses.
GSE62951 CVMHuman Fatty-liver 8 1 To determine whether expression microRNAs (miRNAs) in visceral adipose tissue (VAT) is altered in human non-alcoholic fatty liver disease (NAFLD), we first performed miRNA profiling of VAT from subjects with (n=15, macroscopic liver fat >30%) or without (<5%, non-NAFLD, n=15) NAFLD. VAT miRNA expression profiles in the two groups were similar except for a single miRNA, miR-192*, which was 1.9-fold increased in NAFLD. We next overexpressed miR-192* in cultured human adipocytes, measured its effect on the cellular triglyceride content, and characterized these adipocytes by transcriptomic profiling followed by pathway analysis, qPCR and quantification of select cellular proteins.
GSE63055 CVMHuman CVD 57 3 We apply the cellular reprogramming experimental paradigm to two disorders caused by symmetrical copy number variations (CNV) of 7q11.23 and displaying a striking combination of shared as well as symmetrically opposite phenotypes: Williams Beuren syndrome (WBS) and 7q microduplication syndrome (7dupASD). Through a uniquely large and informative cohort of transgene-free patient-derived induced pluripotent stem cells (iPSC), along with their differentiated derivatives, we find that 7q11.23 CNV disrupt transcriptional circuits in disease-relevant pathways already at the pluripotent state. These alterations are then selectively amplified upon differentiation into disease-relevant lineages, thereby establishing the value of large iPSC cohorts in the elucidation of disease-relevant developmental pathways. In addition, we functionally define the quota of transcriptional dysregulation specifically caused by dosage imbalances in GTF2I (also known as TFII-I), a transcription factor in 7q11.23 thought to play a critical role in the two conditions, which we found associated to key repressive chromatin modifiers. Finally, we created an open-access web-based platform (accessible at http://bio.ieo.eu/wbs/ ) to make accessible our multi-layered datasets and integrate contributions by the entire community working on the molecular dissection of the 7q11.23 syndromes.
GSE63067 CVMHuman fatty liver 18 2 Global gene expression patterns of 2 human steatosis and 9 human non-alcoholic steatohepatitis (NASH) together with their respective control patterns were analyzed to define the non-alcoholic fatty liver disease (NAFLD) progression molecular characteristics and to define NASH early markers from steatosis.
GSE63881 CVMHuman CVD 341 1 Transcriptional profile in Kawasaki patients at acute and convalescent phase with different clinical outcomes were investigated.
GSE64233 CVMHuman Obesity 22 4 The proinflammatory cytokine tumor necrosis factor (TNF) plays a central role in low-grade adipose tissue inflammation and development of insulin resistance during obesity. In this context, nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), is directly involved and required for the acute activation of the inflammatory gene program. Here we show that the major transactivating subunit of NF?B, v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), is also required for acute TNF-induced suppression of adipocyte genes. Notably, this repression does not involve RELA binding to the associated enhancers but rather loss of cofactors and enhancer RNA (eRNA) selectively from high occupancy sites within super-enhancers. Based on these data we have developed models that with high accuracy predict which enhancers and genes are repressed by TNF in adipocytes. We show that these models are applicable to other cell types where TNF represses genes associated with super-enhancers in a highly cell type-specific manner. Our results propose a novel paradigm for NF?B-mediated repression, whereby NF?B selectively redistributes cofactors from high occupancy enhancers, thereby specifically repressing super-enhancer-associated cell identity genes.
GSE64567 CVMHuman Obesity 64 1 Total RNA obtained from human fasted subcutaneous abdominal adipose tissue (FAT) was used to measure genome-wide gene expression. Expression values which were significantly present were standardized by quantile normalization and correlated with clinical data.
GSE65354 CVMHuman CVD 4 1 Pro-inflammatory response of VSMCs is triggered by endothelial damage and a causative step for thrombosis and neointimal thickening in the arterial vessels. Therefore, we investigate a role of cytosolic Hsp60 as a novel pro-inflammatory mediator in VSMCs. Hsp60 was detected in the cytosol of VSMCs. The selective depletion of cytosolic Hsp60 in VSMCs reduced the IKK activation, repressed the induction of NF-?B-dependent pro-survival genes (MnSOD and Bfl-1/A1), and enhanced apoptotic death in response to TNF-a. Moreover, a quantitative RNA sequencing revealed that the expression of 75 genes among the 774 TNF-a-inducible genes was significantly reduced by the depletion of cytosolic Hsp60. In particular, the expression of pro-inflammatory cytokines/chemokines, such as CCL2, CCL20, and IL-6, was regulated by the cytosolic Hsp60 in VSMCs. Finally, the depletion of cytosolic Hsp60 markedly inhibited the neointimal thickening in the balloon-injured arterial vessels by inducing apoptotic cell death and inhibiting chemokine production. This study provides the first evidence that cytosolic Hsp60 could be a therapeutic target for preventing inflammation-driven VSMC hyperplasia in the injured vessels.
GSE65446 CVMHuman CVD 10 1 To explore the primary cause of Dilated Cardiomyopathy in heart samples from DCM-diagnosed patients who had undergone heart transplant (hDCM), we set out to identify differentially expressed genes by massively parallel sequencing of heart samples.
GSE65561 CVMHuman CKD 18 4 Chronic inflammation leading to pro-inflammatory macrophage infiltration contributes to the pathogenesis of type 2 diabetes and subsequently the development of diabetic nephropathy. Mesenchymal stem cells (MSCs) possess unique immunomodulatory and cytoprotective properties making them an ideal candidate for therapeutic intervention\r\nWe used microarrays to detail changes in the gene expression profile of monocytes isolated from type 2 diabetic patients with end-stage renal disease and non-diabetic control subjects following co-culture with MSCs.
GSE65705 CVMHuman CVD 33 2 Recent technological advances have made transcriptome sequencing (RNA-seq) possible in cells with low RNA copy number including platelets. Resulting studies have used RNA-seq in platelets isolated from healthy individuals to characterize the platelet transcriptome. However, platelets, possibly through gene expression changes, contribute to the etiology of and response to cardiovascular disease and events. To address this, we performed the largest human platelet RNA-seq analysis to date in 34 platelet samples: 16 ST-segment elevation myocardial infarction (STEMI), 16 non-STEMI (NSTEMI), and 2 controls.
GSE65761 CVMHuman nomodel 3 0 Phospholamban R14del mutazion (PLN-R14del) has been identified in a large family pedigree in which heterozygous carriers exhibited inherited dilated cardiomyopathy (DCM) and death by middle age. To better understand the causal link between the mutations in PLN and DCM pathology, we derived induced pluripotent stem cells from a DCM patient carrying the PLN R14del mutation. We showed that iPSC-derived cardiomyocytes recapitulated the DCM-specific phenotype and demonstrated that either TALEN-mediated genetic correction or combinatorial gene therapy resulted in phenotypic rescue. Our findings offer novel insights into the pathogenesis caused by mutant PLN and point to the development of potential new therapeutics of pathogenic genetic variants associated with inherited cardiomyopathies.
GSE65802 CVMHuman nomodel 21 0 Identification of the inflammatory signature in visceral adipose tissue CD14+ cells (adipose tissue macrophage)\r\nTotal RNA obtained from CD14+ cells (Immunoselcted cells from stromal adipose tissue cells)
GSE65907 CVMHuman nomodel 2112 0 Genetics of gene expression (eQTLs or expression QTLs) has proved an indispensable tool for understanding biological pathways and pathomechanisms of trait associated SNPs. However, power of most genome-wide eQTL studies is still limited. We performed a large eQTL study in peripheral blood mononuclear cells of 2,112 individuals increasing the power to detect trans-effects genome-wide. Going beyond univariate SNP-transcript associations, we analyse relations of eQTLs to biological pathways, polygenetic effects of expression regulation, trans-clusters, and enrichment of co-localised functional elements. We found eQTLs for about 85% of analysed genes, 18% of genes were trans-regulated. Local eSNPs were enriched up to a distance of 5 MB to the transcript challenging typically implemented ranges of cis-regulations. Pathway enrichment within regulated genes of GWAS-related eSNPs supported functional relevance of identified eQTLs. We demonstrate that nearest genes of GWAS-SNPs might often be misleading functional candidates. We identified novel trans-clusters of potential functional relevance for GWAS-SNPs of several phenotypes including obesity-related traits, HDL-cholesterol levels, and haematological phenotypes. We used chromatin immunoprecipitation data for demonstrating biological effects. We show for strongly heritable transcripts that a considerable gap still exists between total heritability resulting from all trans-chromosomes and explained variance of all identified trans-eSNPs. In contrast, the vast majority of most cis-heritability of these genes is already explained. Dissection of co-localised functional elements indicated a prominent role of SNPs in loci of pseudogenes and non-coding RNAs for the regulation of coding genes. In summary, our study substantially increases the catalogue of human eQTLs and improves our understanding of the complex genetic regulation of gene-expression, pathways and disease related processes.
GSE66175 CVMHuman Diabetes 480 21 The objective of this study was to examine relationships between weight loss through changes in lifestyle and peripheral blood gene expression profiles. Substantial weight loss (-15.2+3.8%) in lifestyle participants was associated with improvement in selected cardiovascular risk factors and significant changes in peripheral blood gene expression from pre- to post-intervention: 132 unique genes showed significant expression changes related to immune function and inflammatory responses involving endothelial activation.\r\nIn contrast, participants losing minimal weight (-3.1+2.5%) showed only minor changes in cardiovascular risk factors and markers of inflammation, and no changes in gene expression compared to non-intervention controls after 1 year. Weight loss (>10%) during lifestyle modification is associated with down-regulation of genetic pathways governing interactions between circulating immune cells and the vascular endothelium and may be required to successfully reduce CVD risk.
GSE66306 CVMHuman Obesity 38 1 Genome-wide expression profiles in peripheral monocytes (PM) from 19 obese women before and 3 months after bariatric surgery using the RNA-seq technology. This dataset is linked to the dataset GSE65540 providing expression profiles in subcutaneous adipose tissue (SAT) in the same population. Due to exclusion of some individuals for technical reasons, the overlap between the 2 datasets is of 18 women.
GSE66360 CVMHuman CVD 99 1 Despite the significant reduction in the overall burden of cardiovascular disease (CVD) over the past decade, CVD still accounts for a third of all deaths in the United States and worldwide each year. While efforts to identify and reduce risk factors for atherosclerotic heart disease (i.e. hypertension, dyslipidemia, diabetes mellitus, cigarette smoking, inactivity) remain the focus of primary prevention, the inability to accurately and temporally predict acute myocardial infarction (AMI) impairs our ability to further improve patient outcomes. Our diagnostic evaluation for the presence of coronary artery disease relies on functional testing, which detects flow-limiting coronary stenosis, but we have known for decades that most lesions underlying AMI are only of mild to moderate luminal narrowings, not obstructing coronary blood flow. Accordingly, there is a dire need of improved diagnostics for underlying arterial plaque dynamics, fissure and rupture. Here we describe the designation of a specific gene expression pattern acting as a molecular signature for acute myocardial infarction present in whole blood of patients that was determined using microarray analysis of enriched circulating endothelial cells (CEC).\r\nWe isolated circulating endothelial cells from patients experience acute myocardial infartion and healthy cohorts, and measured gene expression using the HG-133U_PLUS_2 microarray
GSE66413 CVMHuman Diabetes 23 1 Type 1 diabetes (T1D) is a polygenic autoimmune disorder caused by autoreactive T cells that recognize pancreatic islet antigens and subsequently destroy insulin-producing ß-cells. Pancreatic lymph nodes (PLN) are an essential site for the development of T1D, where tolerance to pancreatic self-antigens is first broken and the autoimmune responses are amplified. The purpose of this study was to identify candidate genes and pathways in the PLN that may contribute to the pathogenesis of T1D.
GSE66785 CVMHuman Diabetes 4 1 A previous study from this laboratory demonstrated that up-regulating HNF4a could reverse the malignant phenotypes of HCC by inducing redifferentiation of HCC cells to hepatocytes. To study the mechanisms of the hepatic differentiation effect by HNF4a, we used the cDNA microarray to detect differential gene expression profiles of Hep3B infected with AdHNF4a and AdGFP.\r\nExpression profile analysis revealed that HNF4a positively regulated 1218 mRNAs and negatively regulated 1411 mRNAs for more than 2 times. The pathway analysis for the differential genes showed that the genes were involved in Complement and coagulation cascades, metabolism, Type II diabetes mellitus, Pathways in cancer etc.
GSE67279 CVMHuman Obesity 40 1 Background/aims: Serum concentrations of the hepatokine fibroblast growth factor (FGF) 21 are elevated in obesity, type-2 diabetes, and the metabolic syndrome. We asked whether FGF21 levels differ between subjects with metabolically healthy vs. unhealthy obesity (MHO vs. MUHO) opening the possibility that FGF21 is a cross-talker between liver and adipose tissue in MUHO. Furthermore, we studied the effects of chronic FGF21 treatment on adipocyte differentiation, lipid storage, and adipokine secretion.\r\nMethods/study design: In 20 morbidly obese donors of abdominal subcutaneous fat biopsies discordant for their whole-body insulin sensitivity (hereby classified as MHO or MUHO subjects), serum FGF21 was quantified. The impact of chronic FGF21 treatment on differentiation, lipid accumulation, and adipokine release was assessed in isolated preadipocytes differentiated in vitro.\r\nResults: Serum FGF21 concentrations were more than two-fold higher in MUHO as compared to 37 MHO subjects (457 ±378 vs. 211 ±123 pg/mL; p<0.05). FGF21 treatment of human preadipocytes for the entire differentiation period was modestly lipogenic (+15%; p<0.05), reduced the expression of key adipogenic transcription factors (PPARG and CEBPA, -15% and -40%, respectively; p<0.01 both), reduced adiponectin expression (-20%; p<0.05), markedly reduced adiponectin release (-60%; p<0.01), and substantially increased leptin (+60%; p<0.01) and interleukin-6 (+50%; p<0.001) release.\r\nInterpretation/conclusions: The hepatokine FGF21 exerts weak lipogenic and anti-adipogenic actions and marked adiponectin-suppressive and leptin and interleukin-6 release-promoting effects in human differentiating preadipocytes. Together with the higher serum concentrations in MUHO subjects, our findings reveal FGF21 as a circulating factor promoting the development of metabolically unhealthy adipocytes.
GSE6751 CVMHuman CVD 59 3 Periodontal infections have been associated with systemic inflammation and risk for atherosclerosis and vascular disease. We investigated the effects of comprehensive periodontal therapy on gene expression of peripheral blood monocytes. Approximately 1/3 of the patients showed substantial changes in expression in genes relevant to innate immunity, apoptosis, and cell signaling. We concluded that periodontal therapy may alter monocytic gene expression in a manner consistent with a systemic anti-inflammatory effect.
GSE67543 CVMHuman Diabetes 24 2 Understanding distinct gene expression patterns of normal adult and developing fetal human pancreatic a and b cells is crucial for developing stem cell therapies, islet regeneration strategies, and therapies designed to increase b cell function in patients with diabetes (type 1 or 2). Toward that end, we have developed methods to highly purify a, b, and d cells from human fetal and adult pancreata by intracellular staining for the cell-specific hormone content, sorting the sub-populations by flow cytometry and, using next generation RNA sequencing, we report on the detailed transcriptomes of fetal and adult a and b cells. We observed that human islet composition was not influenced by age, gender, or body mass index and transcripts for inflammatory gene products were noted in fetal b cells. In addition, within highly purified adult glucagon-expressing a cells, we observed surprisingly high insulin mRNA expression, but not insulin protein expression. This transcriptome analysis from highly purified islet a and b cell subsets from fetal and adult pancreata offers clear implications for strategies that seek to increase insulin expression in type 1 and type 2 diabetes.
GSE67738 CVMHuman Diabetes 38 2 We have performed gene expression microarray analysis to profile transcriptomic signatures between insulin resistance high risk subjects and insulin resistance low risk subjects
GSE68049 CVMHuman Diabetes 189 3 Background: Blocking the action of the pro-inflammatory cytokine interleukin-1 (IL-1) reduces beta-cell secretory dysfunction and apoptosis in vitro, diabetes incidence in animal models of Type 1 diabetes mellitus (T1D), and glycaemia via improved beta-cell function in patients with T2D. We hypothesised that canakinumab, a monoclonal antibody to IL-1B, improves beta-cell function in patients with new-onset T1D. Methods: In an individually randomised, two-group parallel trial involving 12 sites in US, 69 patients aged 6-45 with T1D, < 12 weeks of symptoms, and assigned by centralised computer-generated blocked randomisation with locked computer-file concealment to treatment with 2 mg/kg (maximum 300 mg) canakinumab (n=45) or placebo (n=22) monthly for 12 months as add-on to conventional therapy. Participants and care-givers, but not data monitoring unit, were masked to group assignment. The primary end-point was change in the two-hour area-under-the-curve C-peptide response to MMT 12 months.
GSE68055 CVMHuman Obesity 13 1 Rimonabant was prescribed to eight patients, admitted to the Overweight Study Unit at the Department of Medicine, Karolinska University Hospital. All patients had a BMI > 35 kg/m2, were treated on clinical indications (metabolic and mechanical disability) and without mental disturbances. Blood samples were collected before treatment and at the first clinical control, when the patients had received rimonabant, 20 mg daily, for 4 weeks.
GSE68183 CVMHuman Diabetes 6 1 Diabetes Mellitus (DM) is a chronic, severe disease rapidly increasing in incidence and prevalence and is associated with numerous complications. Patients with DM are at high risk of developing diabetic foot ulcers (DFU) that often lead to lower limb amputations, long term disability, and a shortened lifespan. Despite this, the effects of DM on human foot skin biology are largely unknown. Thus, the focus of this study was to determine whether DM changes foot skin biology predisposing it for healing impairment and development of DFU. Foot skin samples were collected from 20 patients receiving corrective foot surgery and, using a combination of multiple molecular and cellular approaches we performed comparative analyses of non-ulcerated non-neuropathic diabetic foot skin (DFS) and healthy non-diabetic foot skin (NFS). MicroRNA (miR) profiling of laser captured epidermis and primary dermal fibroblasts from both DFS and NFS samples identified 5 miRs de-regulated in the epidermis of DFS though none reached statistical significance. MiR-31-5p and miR-31-3p were most profoundly induced. Although none were significantly regulated in diabetic fibroblasts, miR-29c-3p showed a trend of up-regulation, which was confirmed by qPCR in a prospective set of 20 skin samples. Gene expression profiling of full thickness biopsies identified 36 de-regulated genes in DFS (>2 fold-change, unadjusted p-value = 0.05). Of this group, three out of seven tested genes were confirmed by qPCR: SERPINB3 was up-regulated whereas OR2A4 and LGR5 were down-regulated in DFS. However no morphological differences in histology, collagen deposition, and number of blood vessels or lymphocytes were found. No difference in proliferative capacity was observed by quantification of Ki67 positive cells in epidermis. These findings suggest DM causes only subtle changes to foot skin. Since morphology, mRNA and miR levels were not affected in a major way, additional factors, such as neuropathy, vascular complications, or duration of DM, may further compromise tissue’s healing ability leading to development of DFUs.
GSE68526 CVMHuman Obesity 121 1 Individual differences in peripheral blood transcriptomes in older adults as a function of demographic, socio-economic, psychological, and health history characteristics.
GSE68544 CVMHuman Obesity 41 2 Brown adipose tissue (BAT) holds therapeutic potential for obesity and metabolic syndrome via increasing energy expenditure. Both inter- and intra-individual differences contribute to heterogeneity in human BAT and potentially to differential thermogenic capacity in human populations. Here, we demonstrated the generation of brown and white preadipocyte clones from human neck fat and characterized their adipogenic differentiation and thermogenic function. Combining a UCP1 reporter system and gene expression profiling, we defined novel sets of gene signatures in human preadipocytes that could predict the thermogenic potential of mature adipocytes. Knocking out the positive UCP1 regulators, PREX1 and EDNRB, in brown preadipocytes by CRISPRs markedly abolished the high level of UCP1 in mature brown adipocytes. Finally, we showed the ability to prospectively isolate adipose progenitors with great thermogenic potential. These data provide new insights into the cellular heterogeneity in human fat and offer clinically relevant gene targets that mark thermogenically competent preadipocytes.
GSE68759 CVMHuman Obesity 198 3 In a randomized controlled dietary intervention study we compared an isocaloric Healthy Nordic diet with the average Nordic diet for influence on peripheral blood mononuclear cells (PBMC) gene expression. We studied obese adults with features of the metabolic syndrom, n=66. There was no significant difference in age, BMI, or gene expression between the groups before the intervention. The intervention lasted for 18-24 weeks.
GSE68826 CVMHuman CKD 11 3 Abstract: Human kidney function declines with age, accompanied by stereotyped changes in gene expression and histopathology, but the mechanisms underlying these changes are largely unknown. We compared age-associated changes in global gene expression patterns in the human kidney with genome-wide maps of transcription factor occupancy in human cell lines to identify potential regulators of gene expression changes in the aging kidney. The strongest associations involved three inflammation-associated transcription factors: NF?B, STAT1 and STAT3. We found that the activity of these transcription factors increases with age in epithelial compartments of the renal cortex. Stimulation of renal tubular epithelial cells with the inflammatory cytokines IL-6 (a STAT3 activator), IFN-? (a STAT1 activator), or TNFa (an NF?B activator) recapitulated age-associated gene expression changes. We found that common DNA variants in the two genes that encode the subunits of the canonical NF?B transcription factor (RELA and NFKB1) showed significant associations with kidney function and chronic kidney disease in gene association studies, providing the first evidence for a direct link between genetic variation in NF?B and individual differences in age-related phenotypes in the kidney. Our results point to chronic inflammation, mediated by NF?B, STAT1 and STAT3, as a dominant mechanism influencing gene expression changes during kidney aging.
GSE68940 CVMHuman CKD 12 2 Abstract: Human kidney function declines with age, accompanied by stereotyped changes in gene expression and histopathology, but the mechanisms underlying these changes are largely unknown. We compared age-associated changes in global gene expression patterns in the human kidney with genome-wide maps of transcription factor occupancy in human cell lines to identify potential regulators of gene expression changes in the aging kidney. The strongest associations involved three inflammation-associated transcription factors: NF?B, STAT1 and STAT3. We found that the activity of these transcription factors increases with age in epithelial compartments of the renal cortex. Stimulation of renal tubular epithelial cells with the inflammatory cytokines IL-6 (a STAT3 activator), IFN-? (a STAT1 activator), or TNFa (an NF?B activator) recapitulated age-associated gene expression changes. We found that common DNA variants in the two genes that encode the subunits of the canonical NF?B transcription factor (RELA and NFKB1) showed significant associations with kidney function and chronic kidney disease in gene association studies, providing the first evidence for a direct link between genetic variation in NF?B and individual differences in age-related phenotypes in the kidney. Our results point to chronic inflammation, mediated by NF?B, STAT1 and STAT3, as a dominant mechanism influencing gene expression changes during kidney aging.
GSE68941 CVMHuman CKD 12 2 Abstract: Human kidney function declines with age, accompanied by stereotyped changes in gene expression and histopathology, but the mechanisms underlying these changes are largely unknown. We compared age-associated changes in global gene expression patterns in the human kidney with genome-wide maps of transcription factor occupancy in human cell lines to identify potential regulators of gene expression changes in the aging kidney. The strongest associations involved three inflammation-associated transcription factors: NF?B, STAT1 and STAT3. We found that the activity of these transcription factors increases with age in epithelial compartments of the renal cortex. Stimulation of renal tubular epithelial cells with the inflammatory cytokines IL-6 (a STAT3 activator), IFN-? (a STAT1 activator), or TNFa (an NF?B activator) recapitulated age-associated gene expression changes. We found that common DNA variants in the two genes that encode the subunits of the canonical NF?B transcription factor (RELA and NFKB1) showed significant associations with kidney function and chronic kidney disease in gene association studies, providing the first evidence for a direct link between genetic variation in NF?B and individual differences in age-related phenotypes in the kidney. Our results point to chronic inflammation, mediated by NF?B, STAT1 and STAT3, as a dominant mechanism influencing gene expression changes during kidney aging.
GSE68942 CVMHuman CKD 14 4 Abstract: Human kidney function declines with age, accompanied by stereotyped changes in gene expression and histopathology, but the mechanisms underlying these changes are largely unknown. We compared age-associated changes in global gene expression patterns in the human kidney with genome-wide maps of transcription factor occupancy in human cell lines to identify potential regulators of gene expression changes in the aging kidney. The strongest associations involved three inflammation-associated transcription factors: NF?B, STAT1 and STAT3. We found that the activity of these transcription factors increases with age in epithelial compartments of the renal cortex. Stimulation of renal tubular epithelial cells with the inflammatory cytokines IL-6 (a STAT3 activator), IFN-? (a STAT1 activator), or TNFa (an NF?B activator) recapitulated age-associated gene expression changes. We found that common DNA variants in the two genes that encode the subunits of the canonical NF?B transcription factor (RELA and NFKB1) showed significant associations with kidney function and chronic kidney disease in gene association studies, providing the first evidence for a direct link between genetic variation in NF?B and individual differences in age-related phenotypes in the kidney. Our results point to chronic inflammation, mediated by NF?B, STAT1 and STAT3, as a dominant mechanism influencing gene expression changes during kidney aging.
GSE69421 CVMHuman Diabetes 53 1 Differencies between groups between pre and post haematopoietic stem cell transplantation children\r\nImmune reactions are among the most serious complications observed after hematopoietic stem cell transplantation (HSCT) in children. Microarray technique allows for simultaneous assessment of expression of nearly all human genes. The objective of the study was to compare the whole genome expression in children before and after HSCT. A total of 33 children referred for HSCT were enrolled in the study. In 70% of the patients HSCT was performed for the treatment of neoplasms. Blood samples were obtained before HSCT and six months after the procedure. Subsequently, the whole genome expression was assessed in leukocytes using GeneChip® HumanGene 1.0 ST microarray. The analysis of genomic profiles before and after HSCT revealed altered expression of 124 genes. Pathway enrichment analysis revealed upregulation of five pathways after HSCT: allograft rejection, graft-versus-host disease, type I diabetes mellitus, autoimmune thyroid disease and viral myocarditis. The activation of those pathways seems to be related to immune reactions commonly observed after HSCT. Our results contribute to better understanding of the genomic background of the immunologic complications of HSCT.
GSE69438 CVMHuman CKD 42 7 We identified EGF as the top candidates predicting kidney function through an intrarenal transcriptome-driven approach, and demonstrated it is an independent risk predictor of CKD progression and can significantly improve prediction of renal outcome by established clinical parameters in diverse populations with CKD from a wide spectrum of causes and stages
GSE69528 CVMHuman Diabetes 138 1 Melioidosis, caused by Gram negative bacteria Burkholderia pseudomallei, is a major type of community-acquired septicemia in Southeast Asia and Northern Australia with high mortality and morbidity rate. More accurate and rapid diagnosis is needed for improving the management of septicemic melioidosis. We previously identified 37-gene candidate signature to distinguish septicemic melioidosis from sepsis due to other pathogens. The aims of this current study were to independently validate our previous biomarker and consolidate gene selection from each of our microarray data set for establishing a targeted assay for the differential diagnosis of melioidosis. Blood samples were collected from patients who presented with severe inflammatory response syndromes from 3 provincial hospitals in Northeast of Thailand during September 2009 and November 2011. Only culture-confirmed sepsis were included in the study (n=166). We generated a new microarray dataset comprising of 29 patients with septicemic melioidosis and 54 patients with sepsis due to other pathogens. Validation of the 37-gene signature using this new dataset demonstrated the prediction accuracy of approximately 80% for detecting type of sepsis. In order to develop a nanoliter-scale high throughput PCR technology, we further identified additional gene signature from this new microarray dataset and by revisiting our published data. Altogether 85 genes including 6 housekeeping genes were selected. Using multi-steps iteration approach we could reduce the number of biomarkers to 12 genes while the performance is comparable to that of the full panel. The high performance (accuracy >70%) of this 12-gene signature could be validated in a second independent set of samples. The 12-gene panel identified by our study provides high performance for the differential diagnosis of septicemic melioidosis. This finding will be useful for improving the management of septicemic melioidosis in term of diagnosis, treatment and follow up.
GSE69889 CVMHuman Diabetes 18 5 The molecular clock is a transcriptional oscillator present in brain and peripheral cells that coordinates behavior and physiology with the solar cycle. Here we reveal that the clock gates insulin secretion through genome-wide transcriptional control of the pancreatic exocyst across species. Clock transcription factors bind to unique enhancer sites in cycling genes in beta cells that diverge from those in liver, revealing the dynamics of inter-tissue clock control of genomic and physiologic processes important in glucose homeostasis.
GSE70493 CVMHuman Diabetes 63 1 Gestational diabetes mellitus (GDM) affects approximately 18% of pregnancies in the United States and increases the risk of adverse health outcomes in the offspring. These adult disease propensities may be set by anatomical and molecular alterations in the placenta associated with GDM. To assess the mechanistic aspects of fetal programming, we measured genome-wide methylation (Infinium HumanMethylation450 Beadchips) and expression (Affymetrix Transcriptome Microarrays) in placental tissue of 41 GDM cases and 41 matched pregnancies without maternal complications from the Harvard Epigenetic Birth Cohort. Specific transcriptional and epigenetic perturbations associated with GDM status included alterations in the major histocompatibility complex (MHC) region, which were validated in an independent cohort, the Rhode Island Child Health Study. Gene ontology enrichment among gene regulation influenced by GDM revealed an over-representation of immune response pathways among differential expression, reflecting these coordinated changes in the MHC region. Our study represents the largest investigation of transcriptomic and methylomic differences associated with GDM, providing comprehensive insight into the molecular basis of GDM induced fetal (re)programming.
GSE70528 CVMHuman CKD 19 2 Genes related to sleep and wakefulness were evaluated by RNA microarray in patients, including CKD,HD patients and control subjects.
GSE70529 CVMHuman Obesity 36 3 The purpose of this study was to evaluate the effect of progressive weight loss (5, 10, 15% weight loss) on metabolic function such as multi-organ insulin sensitivity and beta-cell function in obese people. We conducted microarray analysis to determine the effect of progressive weight loss on adipose tissue gene expression profile.
GSE71416 CVMHuman Obesity 20 1 Adipose tissues play an important role in the pathophysiology of obesity-related disease including type 2 diabetes. To describe gene expression patterns and functional pathways in obesity-related type 2 diabetes, we performed global transcript profiling of omental adipose tissue in morbidly obese individuals with or without diabetes.
GSE71731 CVMHuman Fatty-liver 8 1 Background: Studies in mice have shown that PPARa is an important regulator of lipid metabolism in liver and a key transcription factor involved in the adaptive response to fasting. However, much less is known about the role of PPARa in human liver. Here we set out to study the function of PPARa in human liver via analysis of whole genome gene regulation in human liver slices treated with the PPARa agonist Wy14643.\r\nResults: Quantitative PCR indicated that PPARa is well expressed in human liver and human liver slices and that the classical PPARa targets PLIN2, VLDLR, ANGPTL4, CPT1A and PDK4 are robustly induced by PPARa activation. Transcriptomics analysis indicated that 617 genes were upregulated and 665 genes were downregulated by PPARa activation (q value<0.05). Many genes induced by PPARa activation were involved in lipid metabolism (ACSL5, AGPAT9, FADS1, SLC27A4), xenobiotic metabolism (POR, ABCC2, CYP3A5) or the unfolded protein response, whereas most of the downregulated genes were involved in immune-related pathways. Among the most highly repressed genes upon PPARa activation were several chemokines (e.g. CXCL9-11, CCL8, CX3CL1, CXCL6), interferon ?-induced genes (e.g. IFITM1, IFIT1, IFIT2, IFIT3) and numerous other immune-related genes (e.g. TLR3, NOS2, and LCN2). Comparative analysis of gene regulation by Wy14643 between human liver slices and primary human hepatocytes showed that down-regulation of gene expression by PPARa is much better captured by liver slices as compared to primary hepatocytes. In particular, PPARa activation markedly suppressed immunity/inflammation-related genes in human liver slices but not in primary hepatocytes. Finally, several putative new target genes of PPARa were identified that were commonly induced by PPARa activation in the two human liver model systems, including TSKU, RHOF, CA12 and VSIG10L.\r\nConclusion: Our manuscript demonstrates the suitability and superiority of human liver slices over primary hepatocytes for studying the functional role of PPARa in human liver. Our data underscore the major role of PPARa in regulation of hepatic lipid and xenobiotic metabolism in human liver and reveal a marked immuno-suppressive/anti-inflammatory effect of PPARa in human liver slices that may be therapeutically relevant for non-alcoholic fatty liver disease.
GSE72158 CVMHuman Obesity 84 1 The main aim of this experiment was to investigate gene expression on human subcutaneous adipose tissue following bariatric surgery. Our questions consisted in understanding how gene expression was linked to clinical parameters of obese patients and whether this drastic weight loss was discriminated this data.
GSE73378 CVMHuman CVD 210 1 Investigation of gene expression profiles in blood of previous aSAH patients, aiming to gain insight into the pathogenesis of IA and aSAH, and to make a first step towards improvement of aSAH risk prediction. The results indicate that no gene expression differences are present in blood of previous aSAH patients compared to controls, besides one differentially co-expressed gene network without a clear relevant biological function.
GSE75886 CVMHuman CKD 29 2 Secondary hyperparathyroidism is well known complication manifested in end-stage renal disease (ESRD). Both nodular and diffuse parathyreoid hyperplasia occur in ESRD patients. Distinct molecular mechanisms involved in parathyreoid hyperplasia remain poorly understood. Microarray screening proved homogeneity of gene transcripts in hemodialysis patients as compared to transplant cohort and primary hyperparathyreoidism, therefore further studies were performed in hemodialysis patints only. Enrichment analysis conducted on 485 differentially expressed genes between nodular and diffuse parathyreoid hyperplasia revealed highly significant differences in GO terms and KEGG database in ribosome structure (p=3.70-18). Next, RT-qPCR validation of microarray analysis proved higher expression of RAN guanine nucleotide release factor (RANGRF, p<0.001), calcyclin binding protein (CACYBP, p<0.05) and exocyst complex component 8 (EXOC8, p<0.05) and lower expression of peptidylprolyl cis/trans isomerase, NIMA-interacting 1 (PIN1, p<0.01) mRNA in nodular hyperplasia. Multivariate analysis revealed RANGRF and PIN1 expression along with parathyroid weight to be associated with nodular hyperplasia. Higher expression of genes associated with ribosomal structure and function underline extended translation mechanisms involved in parathyreoid nodular formation in long-term hemodialysis treated patients.
GSE76268 CVMHuman Diabetes 15 1 Objective: Although glucagon-secreting a-cells and insulin-secreting ß-cells have opposing functions in regulating plasma glucose levels, the two cell types share a common developmental origin and have overlaps in their transcriptome and epigenome profiles. Notably, destruction of one of these cell populations can stimulate repopulation via transdifferentiation of the other cell type, at least in mice, suggesting plasticity between these cell fates. Furthermore, dysfunction of both a- and ß-cells contributes to the pathophysiology of type 1 and type 2 diabetes, and ß-cell de-differentiation has been proposed to contribute to type 2 diabetes. Our objective was to delineate the molecular properties that maintain islet cell type specification yet allow for cellular plasticity. We hypothesized that correlating cell type-specific transcriptomes with an atlas of open chromatin will identify novel genes and transcriptional regulatory elements such as enhancers involved in a- and ß-cell specification and plasticity.\r\nMethods: We sorted human a- and b-cells and performed the “Assay for Transposase-Accessible Chromatin with high throughput sequencing” (ATAC-seq) and mRNA-seq, followed by integrative analysis to identify cell type-selective gene regulatory regions.\r\nResults: We identified numerous transcripts with either a-cell- or ß-cell-selective expression and discovered the cell type-selective open chromatin regions that correlate with these gene activation patterns. We confirmed cell type-selective expression on the protein level for two of the top hits from our screen. The “group specific protein” (GC; or vitamin D binding protein) was restricted to a-cells, while CHODL (chondrolectin) immunoreactivity was only present in b-cells. Furthermore, a-cell- and ß-cell-selective ATAC-seq peaks were identified to overlap with known binding sites for islet transcription factors, as well as with common single nucleotide polymorphisms (SNPs) previously identified as risk loci for type 2 diabetes.\r\nConclusions: We have determined the genetic landscape of human a- and ß-cells based on chromatin accessibility and transcript levels, which allowed for detection of novel a- and ß-cell signature genes not previously known to be expressed in islets. Using fine-mapping of open chromatin, we have identified thousands of potential cis-regulatory elements that operate in an endocrine cell type-specific fashion.
GSE76490 CVMHuman Obesity 8 4 Fragile X syndrome (FXS) is one of the most prevalent inherited intellectual disabilities. The patients carry the expansion of over 200 CGG repeats located at the 5' untranslated region of fragile X mental retardation 1 (FMR1). As a result, the FMR1 promoter becomes hypermethylated leading to decreased or absent expression of its encoded RNA-binding protein fragile X mental retardation protein (FMRP). We previously generated human induced pluripotent stem (iPS) cells from fibroblasts of a FXS patient (FXS-iPSC) with expanded CGG-repeats at the FMR1 promoter. In the present work, we explored the transcriptional misregulation during the embryonic neurogenesis by in-vitro differentiation of FXS-iPSC into neurons through the intermediate stages. At each differentiation stage, we collected RNA and performed RNA-seq. After an integrated analysis, we found up-regulation of many genes encoding TFs for neuronal differentiation (WNT1, BMP4, POU3F4, TFAP2C, and PAX3), down-regulation of potassium channels (KCNA1, KCNC3, KCNG2, KCNIP4, KCNJ3, KCNK9, and KCNT1) and altered temporal regulation of SHANK1 and NNAT in FXS-iPSC derived neurons, indicating impaired neuronal differentiation and function in FXS patients. Furthermore, we found the cholesterol synthesis genes (e.g., SQLE, LSS, and FASN) are up-regulated during the in-vitro neuronal differentiation of FXS-iPSC, which may contribute to the obesity phenotype of FXS patients. In conclusion, we demonstrated that the FMRP deficiency in FXS patients has significant impact on the gene expression patterns during development, and also discovered many potential candidate genes for the cure of FXS symptoms such as neuronal abnormalities and obesity.
GSE77350 CVMHuman Diabetes 590 2 Application of Systems Genetics analysis for systematic evaluation of candidate causal genes associated with risk of Type 1 Diabetes along with follow-up bioinformatics pathway analysis.
GSE78958 CVMHuman Obesity 424 2 Background: Obesity is a risk factor for breast cancer in postmenopausal women and is associated with decreased survival and less favorable clinical characteristics such as greater tumor burden, higher grade, and poor prognosis, regardless of menopausal status. Despite the negative impact of obesity on clinical outcome, molecular mechanisms through which excess adiposity influences breast cancer etiology are not well-defined.\r\nMethods: Affymetrix U133 2.0 gene expression data were generated for 405 primary breast tumors using RNA isolated from laser microdissected tissues. Patients were classified as normal-weight (BMI<25), overweight (BMI 25-29.9) or obese (BMI>30). Statistical analysis was performed by ANOVA using Partek Genomics Suite version 6.6 using a false discovery rate <0.05 to define significance.\r\nResults: Obese patients were significantly more likely to be diagnosed >50 years or with African American ancestry compared to lean or overweight women. Pathological characteristics, including tumor stage, size or grade, lymph node status, intrinsic subtype, and breast cancer mortality did not differ significantly between groups. No significant gene expression differences were detected by BMI In a non-stratified analysis which included all subtypes or within luminal B, HER2-enriched or basal-like subtypes. Within luminal A tumors, however, 84 probes representing 77 genes from pathways such as cell cycle, p53 and mTOR signaling, tight junctions and a number of cancer associated pathways were differentially expressed.\r\nConclusions: Identification of transcriptome differences in luminal A tumors from normal-weight compared to obese women suggests that obesity alters gene expression within ER+ tumor epithelial cells. Alterations of pathways involved in cell cycle control, tumorigenesis and metabolism may promote cellular proliferation and provide a molecular explanation for less favorable outcome of obese women with breast cancer. Targeted treatments, such as mTOR inhibitors, may allow for improved treatment and survival of obese women, especially African American women, who are more likely to be obese and suffer outcome disparities.
GSE8157 CVMHuman Obesity 43 2 Insulin resistance is a common metabolic abnormality in women with PCOS and leads to an elevated risk of type 2 diabetes. Studies have shown that thiazolidinediones (TZD) improve metabolic disturbances in PCOS patients. We hypothesized that the effect of TZD in PCOS is in part mediated by changes in the transcriptional profile of muscle favoring insulin sensitivity.\r\nUsing Affymetrix microarrays, we examined the effect of pioglitazone (30 mg/day for 16 weeks) on gene expression in skeletal muscle of 10 obese women with PCOS metabolically characterized by a euglycemic-hyperinsulinemic clamp. Moreover, we explored gene expression changes between these PCOS patients before treatment and 13 healthy control women. Treatment with pioglitazone improved insulin-stimulated total, oxidative and non-oxidative glucose metabolism, and reduced fasting serum insulin (all p < 0.05). Global pathway analysis using Gene Map Annotator and Pathway Profiler (GenMAPP 2.1) and Gene Set Enrichment Analysis (GSEA 2.0.1) revealed a significant upregulation of genes involved in mitochondrial oxidative phosphorylation (OXPHOS), ribosomal proteins, mRNA processing reactome, translation factors, and proteasome complexes in PCOS patients after pioglitazone therapy. Quantitative real-time PCR suggested that upregulation of OXPHOS genes was mediated by an increase in PGC-1a expression (p < 0.05). Expression of genes involved in ribosomal proteins and OXPHOS was down-regulated in PCOS patients before treatment compared to matched healthy women using GenMAPP 2.1 and GSEA 2.1.\r\nThese data indicate that pioglitazone therapy restores insulin sensitivity in part by a coordinated upregulation of genes involved in mitochondrial oxidative metabolism and protein biosynthesis in skeletal muscle of PCOS. These transcriptional effects of pioglitazone therapy may contribute to prevent the onset of type 2 diabetes in these women.
GSE9006 CVMHuman Diabetes 234 4 Objective: We hypothesized that type 1 diabetes (T1D) is accompanied by changes in gene expression in peripheral blood mononuclear cells (PBMCs) due to dysregulation of adaptive and innate immunity, counterregulatory responses to immune dysregulation, insulin deficiency and hyperglycemia. Research Design and Methods: Microarray analysis was performed on PBMCs from 43 patients with newly diagnosed T1D, 12 patients with newly diagnosed type 2 diabetes (T2D) and 24 healthy controls. One and four month follow-up samples were obtained from 20 of the T1D patients.\r\nResults: Microarray analysis identified 282 genes differing in expression between newlydiagnosed T1D patients and controls at a false discovery rate of 0.05. Changes in expression of interleukin-1ß (IL1B), early growth response gene 3 (EGR3), and prostaglandin-endoperoxide\r\nsynthase 2 (PTGS2) resolved within four months of insulin therapy and were also observed in T2D suggesting that they resulted from hyperglycemia. With use of a knowledge base, 81/282 genes could be placed within a network of interrelated genes with predicted functions including apoptosis and cell proliferation. IL1B and the MYC oncogene were the most highly-connected genes in the network. IL1B was highly overexpressed in both T1D and T2D, whereas MYC was dysregulated only in T1D.\r\nConclusion: T1D and T2D likely share a final common pathway for beta cell dysfunction that includes secretion of interleukin-1ß and prostaglandins by immune effector cells, exacerbating existing beta cell dysfunction, and causing further hyperglycemia. The results identify several targets for disease-modifying therapy of diabetes and potential biomarkers for monitoring treatment efficacy.
GSE9624 CVMHuman Obesity 11 1 Characterization of genes associated with adipose tissue is key to understanding the pathogenesis of obesity and developing treatments for this disorder. Differential gene expression in the adipose tissue has been described in adulthood but none studies have been developed on childhood. The purpose of this study was to compare gene expression in omental adipose tissue from obese prepubertal and normal weight children. We selected 5 obese (BMI adjusted for age and sex z score >2) and 6 normal weight children. RNA was extracted from omental adipose tissue biopsies and cRNA was hybridizated on the human genome U133 Plus 2.0 Arrays (Affymetrix®). Microarray experiments were performed for each sample, and selected group of gene expression values were confirmed with real-time RT-PCR in 10 obese and 10 normal weigth prepubertal children. 1276 genes were found to be differentially expressed at P<0.05. Of those differential genes, 201 were upregulated (Fc>2) and 42 were downregulated (Fc<-2). Genes involved in metabolic and signalling pathways were altered in childhood obesity.
GSE9820 CVMHuman CVD 153 5 Monocytes and T-cells play an important role in the development of atherosclerotic coronary artery disease (CAD). Differences in transcriptional activity of these cells might reflect the individual's atherosclerotic burden. Transcriptome analysis of circulating mononuclear cells from carefully matched atherosclerotic and control patients will potentially provide insights into the pathophysiology of atherosclerosis and supply biomarkers for diagnostic purposes. From patients undergoing coronary angiography because of anginal symptoms, we carefully matched 18 patients with severe triple-vessel CAD to 13 control patients without signs of CAD on angiography. All patients were on statin and aspirin treatment. RNA from circulating CD4+ T-cells, CD14+ monocytes, lipopolysaccharide-stimulated monocytes, macrophages and CD34+ progenitor cells was subjected to genome-wide expression analysis. Only CD14+ monocytes demonstrated that a small number of genes involved in activation was overexpressed in control patients, which was verified by real-time polymerase-chain reaction. In this pilot study, cautious matching of patients with severe atherosclerotic CAD with control patients without angiographic signs of coronary atherosclerosis did not reveal differences in transcriptional activity in four out of five different mononuclear cell types. In resting monocytes from patients without overt CAD some inflammatory genes were overexpressed as compared to patients with severe CAD. Large inter-individual variability prevented the use of single differentially expressed genes as biomarkers.
GSE9874 CVMHuman CVD 60 2 The project was designed to identify genes with an altered expression in macrophages from subjects with atherosclerosis compared to macrophages from control subjects.
GSE10214 ImmunoMouse Influenza 6 2 Microarray analysis was used to compare differences and similarities in gene expression patterns between memory CD8+ T cells from mice infected with lymphocytic choriomeningitis virus (LCMV) or influenza virus.
GSE10908 ImmunoMouse AD 27 4 In a transgenic mouse model of Alzheimer disease (AD), cleavage of the amyloid precursor protein (APP) by the a-secretase ADAM10 prevented amyloid plaque formation and alleviated cognitive deficits. Furthermore, there was a positive influence of ADAM10 over-expression on neurotransmitter-specific formation of synapses and on synaptic plasticity.\r\nTo assess the influence of ADAM10 on the gene expression profile in the brain we performed microarray analysis using RNA isolated from brains of five month old mice over-expressing either the a-secretase ADAM10 or a dominant-negative mutant (dn) of this enzyme. As compared to non-transgenic wild-type mice, 355 genes were found to be differentially expressed in ADAM10 transgenic mice and 143 genes in dnADAM10 mice. A higher number of genes was found to be differentially regulated in double-transgenic mouse strains additionally expressing the human APP V717I mutant (APP[V717I]). Thus, a-secretase cleavage of over-expressed APP[V717I] alters CNS gene expression additionally.
GSE10953 ImmunoMouse ALS 18 3 Microarray analysis has been applied to the study of ALS in order to investigate gene expression in whole spinal cord homogenates of SOD1 G93A mice and human ALS cases, although the massive presence of glial cells and inflammatory factors has made it difficult to define which gene expression changes were motor neuron specific. Recently, laser capture microdissection (LCM), combined with microarray analysis, has allowed the identification of motor neuron specific changes in gene expression in human ALS cases.\r\nThe aim of the present study is to combine LCM and microarray analysis to study how motor neurons in the spinal cord of transgenic SOD1 G93A mice and transgenic SOD1 WT respond to stimuli determined by the presence of the human mutant protein throughout the evolution of the stages in motor neuron injury
GSE10964 ImmunoMouse COPD 17 3 Analysis of gene expression in lungs of C57BL/6J mice that develop chronic airway disease phenotypes after a single Sendai virus infection, compared with mice treated with UV-inactivated virus.
GSE11148 ImmunoMouse AD 6 1 Regulation of AD-related genes. Presenilins are intramembrane polytopic proteases. These proteases are critical proteins in pathogenesis of Alzheimer's disease. The function of other polytopic proteases expressed in brains is unknown. Proteins that may potentially interact with PS pathway are of interest to elucidate.\r\nIn this project we will determine gene expression patterns in the brains of mice with altered expression of polytopic protease.\r\nWe hypothesize that family of polytopic proteases expressed in brain may potentially interact with presenilin pathway.\r\nWe will examine 4 RNA samples isolated from brains of mice with significant downregulation of polytopic protease and control animals.\r\nTotal RNA was extracted, purified according to the manufacturer's protocol and stored at -80C.
GSE12024 ImmunoMouse SLE 32 2 NZB/WF1 female mice spontaneously develop autoimmune lupus nephritis. Expression profiling of kidney tissue from (a) 12 week NZB/W F1 female mice defined as asymptomatic for lupus nephritis, (b) 36 and 42 week NZB/W F1 female mice defined as diseased/symptomatic for lupus nephritis and (c) 36 and 42 week NZB/W F1 female mice that are diseased/symptomatic for lupus nephritis and treated with Sirolimus was carried out. The goal of the study was to identify genes associated with lupus nephritis and modulated by Sirolimus, an inhibitor of mTOR. In addition, lupus nephritis genes resistant to Sirolimus therapy were also identfied
GSE12036 ImmunoMouse COPD 6 1 We have investigated the effects of cigarette smoke exposure in three different strains of mice. DBA/2 and C57Bl/6J are susceptible to smoke and develop different lung changes in response to chronic exposure, while ICR mice are resistant to smoke and do not develop emphysema. The present study was carried out to determine early changes in the gene expression profile of mice exposed to cigarette smoke with either a susceptible or resistant phenotype.
GSE13032 ImmunoMouse Asthma 18 4 Resiquimod is a nucleoside analog belonging to the imidazoquinoline family of compounds which is known to signal through Toll-like receptor 7. Resiquimod treatment has been demonstrated to inhibit the development of allergen induced asthma in experimental models. Despite this demonstrated effectiveness, little is known about the molecular events responsible for this effect. The aim of the present study was to elucidate the molecular processes which were altered following resiquimod treatment and antigen challenge in a mouse model of allergic asthma. Employing microarray analysis, we have characterized the “asthmatic” transcriptome of the murine lung and determined that it includes genes involved in: the control of cell cycle progression, airway remodelling, the complement and coagulation cascades, and chemokine signalling. We have demonstrated that systemic resiquimod administration resulted in the recruitment of NK cells to the lungs of the mice, although no causal relationship between NK cell recruitment and treatment efficacy was found. Furthermore, results of our studies demonstrated that resiquimod treatment resulted in the normalization of the expression of genes involved with airway remodelling and chemokine signalling, and in the modulation of the expression of genes including cytokines and chemokines, adhesion molecules, and B-cell related genes, involved in several aspects of immune function and antigen presentation. Overall, our findings identified several genes, important in the development of asthma pathology, that were normalized following resiquimod treatment thus improving our understanding of the molecular consequences of resiquimod treatment in the lung milieu.
GSE13382 ImmunoMouse Asthma 11 2 Allergen challenge induced mucus metaplasia modify the expression of two transcription factors belonging to the FOXA family: FOXA2 and FOXA3. Foxa2 expression is decreased during allergic airway disease whereas, Foxa3 expression is increased by allergen.\r\nTherefore, we asked whether persistent expression of Foxa2 prevents mucus and whether absence of Foxa3 affects mucus or other features asociated with allergic airway disease.\r\nWe analyzed the effects of these changes in FOXA transcription factor expression using Foxa2 transgenic mice and Foxa3-/- mice. We found that persistent expression of FOXA2 reduced mucus but the absence of FOXA3 had no effect on mucus production induced by allergen challenge.\r\nHowever, the absence of FOXA3 decreased airway hyperreactivity and increased IgE production and eosinophilic inflammation but none of these features were affected by persistent expression of FOXA2. These results indicate that FOXA3 has functions distinct from those of FOXA2 in the allergic response.
GSE13643 ImmunoMouse ALS 9 2 To better understand how the expression of a mutant gene that causes ALS can perturb the normal phenotype of astrocytes, and to identify genes that may have a role in their toxic effect on motor neurons, we used oligonucleotide arrays to compare the global gene expression profiles of glia overexpressing the mutant SOD1G93A protein with two different sets of controls: non-transgenic glia and glia overexpressing the wild type form of the human SOD1 protein (P<0.001) .
GSE13691 ImmunoMouse AD 23 2 Aging and neurodegeneration are often accompanied by a functionally impaired ubiquitin-proteasome system (UPS). In tauopathies and polyglutamine diseases a mutant form of Ubiquitin B, UBB+1, accumulates in disease-specific aggregates. UBB+1 mRNA is generated at low levels in vivo during transcription from the Ubiquitin B locus by molecular misreading. The resulting mutant protein has been shown to inhibit proteasome function. To elucidate causative effects and neuropathological consequences of UBB+1 accumulation, we used a UBB+1 expressing transgenic mouse line, that models UPS inhibition in neurons and exhibits behavioral phenotypes reminiscent of Alzheimer’s disease (AD). In order to reveal affected organs and functions, young and aged UBB+1 transgenic mice were comprehensively phenotyped for more than 240 parameters. This revealed unexpected changes in spontaneous breathing patterns and an altered response to hypoxic conditions. Our findings point to a central dysfunction of respiratory regulation in transgenic mice in comparison to wildtype littermate mice. Accordingly, UBB+1 was strongly expressed in brainstem regions of transgenic mice controlling respiration. These regions included, for example, the medial part of the nucleus of the tractus solitarius and the lateral subdivisions of the parabrachial nuclei. In addition, UBB+1 was also strongly expressed in these anatomical structures of AD patients (Braak stage #6) and was not expressed in non-demented controls. We conclude that long-term UPS inhibition due to UBB+1 expression causes central breathing dysfunction in a transgenic mouse model of AD. The UBB+1 expression pattern in humans is consistent with the contribution of bronchopneumonia as a cause of death in AD patients.
GSE13740 ImmunoMouse Influenza 18 2 Pneumonia is a serious problem worldwide. We recently demonstrated that innate defense mechanisms of the lung are highly inducible against pneumococcal pneumonia. To determine the breadth of protection conferred by stimulation of lung mucosal innate immunity, and to identify cells and signaling pathways activated by this treatment, mice were treated with an aerosolized bacterial lysate, then challenged with lethal doses of bacterial and fungal pathogens. Mice were highly protected against a broad array of Gram-positive, Gram-negative, and Class A bioterror bacterial pathogens, and Aspergillus fumigatus. Protection was associated with rapid pathogen killing within the lungs, and this effect was recapitulated in vitro using a respiratory epithelial cell line. Gene expression analysis of lung tissue showed marked activation of NF-kappaB, Type I and II interferon, and antifungal Card9-Bcl10-Malt1 pathways. Cytokines were the most strongly induced genes, but the inflammatory cytokines TNF and IL-6 were not required for protection. Lung-expressed antimicrobial peptides were also highly upregulated. Taken together, stimulated innate resistance (StIR) appears to occur through the activation of multiple host defense signaling pathways in lung epithelial cells, inducing rapid pathogen killing, and conferring broad protection against virulent bacterial and fungal pathogens. Augmentation of innate antimicrobial defenses of the lungs might have therapeutic value for protection of patients with neutropenia or impaired adaptive immunity against opportunistic pneumonia, and for defense of immunocompetent subjects against a bioterror threat or epidemic respiratory infection.
GSE14431 ImmunoMouse LungDisease 12 3 Background: Microvascular injury and increased vascular leakage are prominent features of the radiation-induced lung injury (RILI) which follows cancer–associated thoracic irradiation. The mechanisms of RILI are incompletely understood and therapeutic strategies to limit RILI are currently unavailable. We established a murine model of radiation pneumonitis in order to assess mechanism-based therapies for RILI-induced inflammation and vascular barrier dysfunction. Based on prior studies, we investigated the therapeutic potential of simvastatin as a vascular barrier protective agent in RILI.\r\nMethods: C57BL6/J mice receiving single dose exposure to 18, 20, 22, or 25 Gy, (n=10/group) were temporally assessed (4-12 weeks) for cellular and biochemical indices of injury present in both bronchoalveolar lavage (BAL) and lung tissues (cytokines, tyrosine nitrosylated proteins, leukocytes, extravasation of Evans blue dye or EBD, BAL albumin, histology). In specific experiments, irradiated mice (25Gy) received simvastatin (10 mg/kg) via intraperitoneal injection three times a week (pre and post irradiation) for 2- 6 weeks post irradiation.\r\nResults. Acute RILI evolved in a dose- and time-dependent fashion. Mice irradiated with 25Gy exhibited modest increases in BAL leukocytes but significant increases in BAL IL-6 (p=0.03) and TNF-a (p=0.01) at 4 weeks compared to controls. Increases in BAL nitrotyrosine content peaked at 6 weeks (p=0.03) and was accompanied by marked nitrotyrosine immunostaining in lung tissues. Indices of increase lung vascular permeability such as EBD extravasation, BAL protein and BAL albumin significantly increased over time beginning at 6 weeks (p>0.002 all) with histological evidence of severe edema formation and airway inflammation. Simvastatin- treated irradiated mice were noted to exhibit marked attenuation of vascular leak with significantly decreased BAL protein (p=0.01) and inflammatory cell infiltration (50% reduction).\r\nConclusion: Simvastatin is a potentially important therapeutic strategy to limit RILI and may influence radiation associated morbidity and mortality.\r\nWe used microarrays to detail the global programme of gene expression induced by radiation in Wild type and the protection of SIMVA
GSE14499 ImmunoMouse AD 26 4 We examined transgenic (TG) mice expressing human APP695 bearing the double Swedish (671KM>NL) and Indiana (717V>F) amyloid precursor protein (APP) mutations. Lentiviral vectors constitutively expressing BDNF-GFP under control of the CMV/ß-actin hybrid promoter or GFP alone were injected into the entorhinal cortices of TG mice bilaterally at age 6 months, a time point by which neuropathological degeneration and cell loss are established. Age-matched wild-type littermates underwent sham surgery or injection of lentivirus expressing GFP into the entorhinal cortices bilaterally.
GSE15318 ImmunoMouse IBD 24 4 Background and Aims: In the interleukin-10-deficient (Il10-/-) mouse model of IBD, 10 quantitative trait loci (QTL) have been shown to be associated with colitis susceptibility by linkage analyses on experimental crosses of highly susceptible C3H/HeJBir (C3Bir)-Il10-/- and partially resistant C57BL/6J (B6)-Il10-/- mice. The strongest locus (C3Bir-derived cytokine deficiency-induced colitis susceptibility [Cdcs]1 on Chromosome [Chr] 3) controlled multiple colitogenic subphenotypes and contributed the vast majority to the phenotypic variance in cecum and colon. This was demonstrated by interval-specific Chr 3 congenic mice wherein defined regions of Cdcs1 from C3Bir or B6 were bred into the IL-10-deficient reciprocal background and altered the susceptible or resistant phenotype. Furthermore, this locus likely acts by inducing innate hypo- and adaptive hyperresponsiveness, associated with impaired NF?B responses of macrophages. The aim of the present study was to dissect the complexity of Cdcs1 by further development and characterization of reciprocal Cdcs1 congenic strains and to identify potential candidate genes in the congenic interval. Material and Methods: In total, 15 reciprocal congenic strains were generated from Il10-/- mice of either C3H/HeJBir or C57BL/6J backgrounds by 10 cycles of backcrossing. Colitis activity was monitored by histological grading. Candidate genes were identified by fine mapping of congenic intervals, sequencing, microarray analysis and a high-throughput real-time RT-PCR approach using bone marrow-derived macrophages. Results: Within the originally identified Cdcs1-interval, three independent regions were detected that likely contain susceptibility-determining genetic factors (Cdcs1.1, Cdcs1.2, and Cdcs1.3). Combining results of candidate gene approaches revealed Fcgr1, Cnn3, Larp7, and Alpk1 as highly attractive candidate genes with polymorphisms in coding or regulatory regions and expression differences between susceptible and resistant mouse strains. Conclusions: Subcongenic analysis of the major susceptibility locus Cdcs1 on mouse chromosome 3 revealed a complex genetic structure. Candidate gene approaches revealed attractive genes within the identified regions with homologs that are located in human susceptibility regions for IBD.
GSE1555 ImmunoMouse AD 6 1 Gene expression changes induced by alpha-secretase cleaved amyloid precursor protein (sAPPalpha) in organotypic hippocampal slice cultures of male, postnatal day 15 mice (C57B6/SJL). Hippocampal slice cultures were treated with phosphate buffered saline (GSM26700, GSM26701, GSM26702) or 1 nM sAPPalpha (GSM26703, GSM26704, GSM26705) for 24 h. Each sample consists of total RNA isolated from 8-12 slices from 4 mice. Data were analyzed with MAS 5.0 and scaled to 2500. sAPPalpha induces the amyloid sequestration protein transthyretin, insulin-like growth factor 2, insulin-like growth factor binding protein 2, and other genes involved in protective pathways such as apoptosis inhibition, detoxification, and retinol transport.
GSE15907 ImmunoMouse Arthritis 681 0 Gene-expression microarray datasets generated as part of the Immunological Genome Project (ImmGen). Primary cells from multiple immune lineages are isolated ex-vivo, primarily from young adult B6 male mice, and double-sorted to >99% purity. RNA is extracted from cells in a centralized manner, amplified and hybridized to Affymetrix 1.0 ST MuGene arrays. Protocols are rigorously standardized for all sorting and RNA preparation. Data is released monthly in batches of cell populations.
GSE16360 ImmunoMouse ALS 16 2 The transgenic mice expressing the human mutated form (G93A) of the SOD1 gene represent a valuable model of Amyotrophic Lateral Sclerosis (ALS). SOD1 is one of the main causative genes of familial ALS which accounts for 10% of cases. These transgenic animals develop a motorneuronal pathology that recapitulates well the neuropathological features occuring in ALS patients, and the progression of the disease can be monitored by a series of motor tests. Gastrocnemius is the first and most affected muscle in the disease, while triceps is relatively spared.\r\nGene expression data of degenerating motor neurons at different disease stages are already available, while gene expression data on the muscle tissue are missing. Our aim is to define the role of muscle in motor neuron degeneration in ALS.
GSE16361 ImmunoMouse ALS 20 3 The transgenic mice expressing the human mutated form (G93A) of the SOD1 gene represent a valuable model of Amyotrophic Lateral Sclerosis (ALS). SOD1 is one of the main causative genes of familial ALS which accounts for 10% of cases. These transgenic animals develop a motorneuronal pathology that recapitulates well the neuropatological features occuring in ALS patients, and the progression of the disease can be monitored by a series of motor tests. Gastrocnemius is first and most affected muscle in the disease, while triceps is relatively spared.\r\nGene expression data of degenerating motor neurons at different disease stages are already available, while gene expression data on the muscle tissue are missing. Our aim is to define the role of muscle in motor neuron degeneration in ALS.
GSE16846 ImmunoMouse PulmonaryFibrosis 6 1 Wildtype mice were given saline or bleomycin by oropharyngeal instillation. After 14 days, during the fibrotic phase of the response, lungs were dissected and total RNA was extracted and used for gene expression profiling. The aim was to identify those genes regulated during the development of fibrosis in this animal model of bleomycin-induced lung fibrosis.
GSE1782 ImmunoMouse AD 64 4 Consolidation of long-term memory (LTM) is a complex process requiring synthesis of new mRNAs and proteins. Many studies have characterized the requirement for de novo mRNA and protein synthesis; however, few studies have comprehensively identified genes regulated during LTM consolidation. We show that consolidation of long-term contextual memory in the hippocampus triggers altered expression of numerous genes encompassing many aspects of neuronal function. Like contextual memory formation, this altered gene expression required NMDA receptor activation and was specific for situations in which the animal formed an association between a physical context and a sensory stimulus. Using a bioinformatics approach, we found that regulatory elements for several transcription factors are over-represented in the upstream region of genes regulated during consolidation of LTM. Using a knock-out mouse, we found that c-rel, one of the transcription factors identified in our bioinformatics study, is necessary for hippocampus-dependent long-term memory formation.
GSE18010 ImmunoMouse 2015Q2 29 3 Polymorphisms in the interleukin-4 receptor a chain (IL-4Ra) have been linked to asthma incidence and severity, but a causal relationship has remained uncertain. In particular, a glutamine to arginine substitution at position 576 (Q576R) of IL-4Ra has been associated with severe asthma, especially in African Americans. We show that mice carrying the Q576R polymorphism exhibited intense allergen-induced airway inflammation and remodeling. The Q576R polymorphism did not affect proximal signal transducer and activator of transcription (STAT) 6 activation, but synergized with STAT6 in a gene target– and tissue-specific manner to mediate heightened expression of a subset of IL-4– and IL-13–responsive genes involved in allergic inflammation. Our findings indicate that the Q576R polymorphism directly promotes asthma in carrier populations by selectively augmenting IL-4Ra–dependent signaling.
GSE18033 ImmunoMouse COPD 56 3 COPD is a disorder characterized by the progressive development of airflow limitation that is not fully reversible. Cigarette smoke has been generally accepted as the most important of many risk factors for the development of COPD.\r\nWe used microarray technology to perform comprehensive gene expression profiling of smoke exposure and cessation effects in mouse muscle tissue.
GSE18597 ImmunoMouse ALS 42 7 Expression profiling of spinal cord from SOD1(G93A) mice and age matched controls at ages 28, 42, 56, 70,98,112, and 126 days of age.\r\nWe used microarrays to determine differential gene expression throughout disease progression in the spinal cord of mutant SOD1(G93A) model of ALS.
GSE18800 ImmunoMouse PulmonaryFibrosis 25 5 We purposed to examine the effect of PGF receptor FP in development of\r\nbleomycin-induced pulmonary fibrosis in mice. We performed gene\r\nexpression analysis in the lung of WT and FP-KO mice on Days 0, 7 and\r\n14. We found out that fibrosis-related genes such as various isoforms\r\nof collagen, which were induced on Day 7 and continued to increase or\r\nremained unchanged on Day 14, were induced to less extent in FP-KO\r\nmice. In contrast, expression of inflammation-related genes peaked on\r\nDay 7 similarly in WT and FP-KO mice. These results suggest that FP\r\nfunctions in fibrosis-phase, not in peak inflammation phase, and\r\nfacilitates fibrogenesis by enhancing expression of fibrosis-related\r\ngenes.
GSE19223 ImmunoMouse Asthma 62 2 Gene expression analysis of Der p 1-treated mouse lungs.\r\nWe developed a new mouse model of allergic airway disease employing the house dust mite allergen Der p 1. This model produces qualitatively and quantitatively different effects in two commonly used inbred strains of mice, C57BL/6J and BALB/cJ, demonstrating that genetic background is an important determinant of response to Der p 1. To identify the genes and pathways associated with inflammation and pathophysiology, we used microarrays and found genes that were shared by both strains or were distinct. Among the latter, we identified three G-protein coupled receptors and a number of other genes and pathways whose expression patterns clearly distinguish the divergent physiologic responses of the two strains. We conclude that genetic background is a strong determinant of the type and intensity of response to Der p 1, including the degree of airway hyper-responsiveness and/or inflammation.
GSE2039 ImmunoMouse ALS 19 1 3 subtypes of cortical projection neurons were purified by fluorescence-activated cell sorting at 4 different stages of development from mouse cortex. A detailed description of the data set is described in Arlotta, P et al (2005).
GSE20959 ImmunoMouse PulmonaryFibrosis 108 6 The aim of our research is to clarify the mechanisms generating heterogeneity in response to C-ion irradiation that arise from individual genetic variations in humans. In this study, we performed whole lung C-ion irradiation using three different strains of mice to examine whether strain-dependent differences in radiation effects occur in high-LET C-ion thoracic irradiation. Murine strain-variance was evaluated by histopathological examination of intra-alveolar hemorrhage that is likely to occur during the early phase after irradiation, and of lung fibrosis during the late phase, occurring more than three months after irradiation. We also performed microarray analysis to identify the key genes that are differentially regulated in different mouse strains after C-ion irradiation and to determine the mechanism of strain-dependent pulmonary damage after high-LET C-ion irradiation.
GSE2172 ImmunoMouse IBD 8 3 Abstract: Interleukin-10-deficient (Il10-/-) mice serve as a model for inflammatory bowel disease (IBD). The severity of colitis strongly depends on the inbred strain carrying the disrupted Il10 gene: C3H/HeJBir (C3) confers disease susceptibility, whereas C57BL/6J (B6) confers resistance. Genome-wide scans with microsatellite markers on segregrating backcross and F2 populations resulted in the detection of ten colitogenic quantitative trait loci (QTL). The aim of this study was to reduce the large number of candidate genes within the QTL intervals by identifying those genes which are located within the candidate gene intervals and which are differentially expressed in the colon of IBD-susceptible and -resistant strains. Using this combination of QTL mapping and microarray analysis, we identified 16 genes which were differentially expressed between B6- and C3-Il10-/- mice and were located within the candidate gene intervals. Three of these genes (Pla2g2a, Gbp1, Cd14) showed prominent differences in expression levels between B6- and C3-Il10-/- as well as between B6 and C3 wildtype mice and were considered to be major candidate genes. Pla2g2a and Gbp1 are known to be polymorphic between C3 and B6 mice. Expression data for Cd14 were confirmed by real-time RT PCR using specified pathogen free and germfree Il10-/- mice. In conclusion, the large number of candidate genes was reduced to three major candidates by using a combination of QTL mapping and microarray analysis. All three genes play an important role in inflammatory processes and immune response.\r\nMaterial & Methods:\r\nTwo independent microarray experiments were performed using SPF mice: 19 for the first experiment (4 C3 WT [GSM39296], 5 C3-Il10-/- [GSM39297], 5 B6 WT [GSM39290], 5 B6-Il10-/- [GSM39291]) and 18 for the second (4 C3 WT [GSM39295], 4 C3-Il10-/- [GSM39294], 5 B6 WT [GSM39288], 5 B6-Il10-/- [GSM39289]). The mice were euthanized by cervical dislocation. Following a ventral midline incision, the colon (including the rectum, but not the anus) was removed and flushed with PBS. Each colon was opened longitudinally with a pair of scissors, further dissected and homogenized using a micropistill in 1.5 ml peqGOLD Trifast FL. RNA was isolated according to the manufacturer´s protocol, and quality was checked using RNA Nano LabChip® technology (Agilent, Böblingen, Germany). For each of the two array experiments, equal amounts (7 micro gram) of RNA were pooled from the four or five animals of each mouse strain, resulting in a total of eight samples.\r\nFor biotin-labeled target synthesis starting from 3-5 µg of total RNA, reactions were performed using standard protocols supplied by the manufacturer (Affymetrix; Santa Clara, CA). Briefly, 3-5 µg total RNA were converted to dsDNA using 100 pmol of a T7T23V primer (Eurogentec; Seraing, Belgium) containing a T7 promoter. The cDNA was then used directly in an in-vitro transcription reaction in the presence of biotinylated nucleotides.\r\nThe concentration of biotin-labeled cRNA was determined by UV absorbance. In all cases, 12.5 µg of each biotinylated cRNA preparation were fragmented and placed in a hybridization cocktail containing four biotinylated hybridization controls (BioB, BioC, BioD, and Cre) as recommended by the manufacturer. Samples were hybridized to an identical lot of Affymetrix MG U74Av2 for 16 hours.\r\nData selection and transformation procedures. For normalization, all array experiments were scaled to a target intensity of 150, otherwise using the default values of the Microarray suite 5.0 (MAS 5.0). Filtering of the results was done as follows: Genes were considered as strong regulated if their fold change was greater than or equal 2 or less than or equal -2, the statistical parameter for a significant change was less than 0.01 (change p-Value for changes called Increased) or greater than 0.99 (change p-Value for changes called Decreased). Additionally, the signal difference of a certain gene was greater than 200.
GSE22307 ImmunoMouse IBD 23 3 Temporal genome profiling of DSS colitis\r\nThe DSS induced mouse colitis model is often used to emulate Ulcerative Colitis (UC) in order understand pathophysiological mechanism of inflammatory bowel disease (IBD). Given the progressive nature of IBD, colon tissue gene expression changes during the evolution of disease, and knowing the changes in gene expression profiles could indentify potential diagnostic markers or additional therapeutic targets for colitis. Therefore, we performed temporal genome expression profiling analysis using the Affymetrix genome wide microarray system to identify broad scale changes in gene expression associated with the development of colitis.
GSE22313 ImmunoMouse 2015Q2 8 1 Sle1a.1 is part of the Sle1a lupus susceptibility locus which results in the production of activated and autoreactive CD4+ T cells as well as a reduction in the peripheral regulatory T cell (Treg) pool. Sle1a.1 CD4+ T cells showed a defective response to retinoic acid (RA) expansion of TGFß-induced Tregs. At the molecular level, Sle1a.1 corresponds to an increased expression of a novel splice isoform of Pbx1, Pbx1-d. Pbx1-d over-expression is sufficient to induce an activated/inflammatory phenotype in Jurkat T cells, and to decrease their apoptotic response to RA. PBX1-d is expressed more frequently in lupus patients than in healthy controls, and its presence correlates with an increased memory T cell population. These findings indicate that Pbx1 is a novel lupus susceptibility gene that regulates T cell activation and tolerance.
GSE22351 ImmunoMouse ALS 6 1 TDP-43, a DNA/RNA binding protein involved in RNA transcription and splicing has been associated with the pathophysiology of neurodegenerative diseases, including ALS. However, the function of TDP-43 in motor neurons remains undefined. Here, we employ both gain- and loss-of-function approaches to determine roles of TDP-43 in motor neurons. Mice expressing human TDP-43 in neurons exhibited growth retardation and premature death that are characterized by abnormal intranuclear inclusions comprised of TDP-43 and Fused in Sarcoma (FUS), and massive accumulation of mitochondria in TDP-43-negative cytoplasmic inclusions in motor neurons, lack of mitochondria in motor axon terminals and immature neuromuscular junctions. Whereas elevated level of TDP-43 disrupts the normal nuclear distribution of Survival Motor Neuron (SMN)-associated Gemini of coiled bodies (GEMs) in motor neurons, its absence prevents the formation of GEMs in the nuclei of these cells. Moreover, transcriptome-wide deep sequencing analysis revealed that decrease in abundance of neurofilament transcripts contributed to the reduction of caliber of motor axons in TDP-43 mice. In concert, our findings indicate that TDP-43 participates in pathways critical for motor neuron physiology, including those that regulate the normal distributions of SMN-associated GEMs in the nucleus and mitochondria in the cytoplasm.
GSE22357 ImmunoMouse 2015Q2 24 7 Epidemiological studies have linked exposure to ambient particulate matter (PM) with increased asthmatic symptoms. Diesel exhaust particles (DEP) are a predominant source of vehicle derived ambient PM, and experimental studies have demonstrated that they may have adjuvant potential when given with an antigen. We previously compared 3 DEP samples: N-DEP, A-DEP, and C-DEP in a murine ovalbumin (OVA) mucosal sensitization model and reported the adjuvant activity to be: C-DEP ˜ A-DEP > N-DEP. The present study analyzed gene expression changes from the lungs of these mice. Transcription profiling demonstrated that all the DEP samples altered cytokine and toll-like receptor pathways regardless of type, with or without antigen sensitization. Further analysis of DEP exposure with OVA showed that all DEP treatments altered networks involved in immune and inflammatory responses. The A- and C-DEP/OVA treatments induced differential expression of apoptosis pathways in association with stronger adjuvant responses, while expression of cell cycle control and DNA damage pathways were also altered in the C-DEP/OVA treatment. This comprehensive approach using gene expression analysis to examine changes at a pathway level provides detailed information on events occurring in the lung after DEP exposure, and confirms that the most bioactive sample induced many more individual genes and changes in immuno-regulatory and homeostatic pathways.
GSE22465 ImmunoMouse AD 10 2 Inhibition of proteasome degradation pathway has been implicated in neuronal cell death leading to neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. Pharmacological proteasomal inhibitors such as lactacystin can induce apoptosis in cultured mouse cortical neurons through the activation of caspase-3. Furthermore, proteasomal inhibitors are also reported to mediate deleterious alterations in cell cycle regulation, inflammatory processes and protein aggregation and trigger the cell death pathway.\r\nWe discovered by microarray analysis that lactacystin treatment modulates the expression of both potentially neuroprotective as well as pro-apoptotic genes in neurons. However, the genes, upon transcriptional modulation, contribute to proteasomal inhibition-induced apoptosis, remains unidentified. By employing microarray analysis to decipher the time-dependent changes in transcription of these genes in cultured cortical neurons, we discovered different groups of genes were transcriptionally regulated at different phases of lactacystin-induced cell death.
GSE22856 ImmunoMouse COPD 8 2 The SWCNTs can induce airway hyper-responsiveness (AHR) and chronic obstructive pulmonary disease (COPD)-like changes in mice model. The SWCNTs can induce clusters of proteinases, chemokines/cytokines, and macrophage receptors triggered signaling, which might play critical roles in the SWCNTs-induced pathological changes, including chronic inflammation and tissues remodeling.\r\nWe used microarrays to detail the global programme of gene expression underlying and identified distinct classes of up-regulated genes during this process.
GSE22971 ImmunoMouse 2015Q2 12 2 Rheumatoid arthritis is an autoimmune disease in which joint inflammation lead to progressive cartilage and bone destruction. Matrix metalloproteinases (MMP) implicated in homeostasis of extracellular matrix (ECM) play a central role in cartilage degradation. The aim of this study was to investigate the role of MMP-8 (collagenase-2) suppression in the K/BxN serum-transfer arthritis model.
GSE23421 ImmunoMouse IBD 6 1 Inflammatory bowel disease (IBD) is a condition characterized by severe intestinal inflammation and immune cell activation. The severity of the disease can be mitigated by compounds which activate peroxisome proliferator-activated receptor gamma (PPAR gamma), a receptor present widely in tissues involved in IBD pathogenesis. Our objective was to assess the affect of macrophage-specific deficiency of PPAR gamma on peripheral and colonic immune populations and colonic gene expression in experimental IBD. Macrophage-specific PPAR gamma-deficient mice (PPAR gamma flfl Lysozyme M Cre+) and control (PPAR gamma flfl Lysozyme M Cre-) littermates were treated with 2.5% dextran sodium sulfate (DSS) for 7 days. Disease activity was recorded daily and immune cell populations in the blood, spleen, mesenteric lymph nodes (MLN), and lamina propria were examined by flow cytometry. Colonic gene expression was assessed by real time PCR and microarray analyses. Our findings show that macrophage PPAR r-deficiency significantly exacerbates DSS inflammation. CD4+CD25+FoxP3+ regulatory T cells (T-regs) were significantly reduced in Cre+ mice, and MLN macrophages and CD40 expression were enhanced. There were significant differences in the number colonic macrophages between Cre+ and Cre- mice, but those from Cre+ mice expressed more CD40, Ly6C, and TLR-4. PPAR r-deficiency also increased the percent of CD8+ T cells in the lamina propria and enhanced colonic interferon gamma expression. Our findings indicate that macrophage PPAR gamma deficiency augments the severity of DSS colitis by reducing peripheral T-regs and increasing colonic macrophage activation and T cell inflammation.
GSE23847 ImmunoMouse AD 6 1 The type III RNase Dicer is responsible for the maturation and function of microRNA (miRNA) molecules in the cell. It is now well documented that Dicer and the fine-tuning of the miRNA gene network are important for neuronal integrity. However, the underlying mechanisms involved in neuronal death, particularly in the adult brain, remain poorly defined. Here, we show that absence of Dicer in the adult forebrain is accompanied by a mixed neurodegenerative phenotype. While neuronal loss is observed in the hippocampus, cellular shrinkage is predominant in the cortex. Interestingly, neuronal degeneration coincides with the hyperphosphorylation of endogenous tau at several epitopes previously associated with neurofibrillary pathology. Transcriptome analysis of enzymes involved in tau phosphorylation identified ERK1 as one of the candidate kinases responsible for this event in vivo. We further demonstrate that miRNAs belonging to the miR-15 family are potent regulators of ERK1 expression in mouse neuronal cells and co-expressed with ERK1/2 in vivo. Last, we show that miR-15a is specifically downregulated in Alzheimer’s disease brain. In sum, these results support the hypothesis that changes in the miRNA network may contribute to a neurodegenerative phenotype by affecting tau phosphorylation.
GSE23914 ImmunoMouse IBD 8 1 BACKGROUND: Appendicitis followed by appendectomy (AA) at a young age protects against later inflammatory bowel disease (IBD). Using a novel murine appendicitis model we earlier demonstrated that AA proffered significant protection against subsequent experimental colitis.\r\nAIM: To delineate genes and biological pathways involved in the protective effect of AA against subsequent colitis using gene set enrichment analysis (GSEA) of DNA microarray data.\r\nMETHODS: Appendicitis and appendicectomy was done (5 week old male BALB/c mice) near the most proximal colon (caecal lymphoid follicles) and colonic samples were harvested from the most distal colon. Two consecutive laparotomies were done in control Sham-Sham (SS) mice. RNA was extracted (TRIzol®) from 4 individual colonic samples per group (AA group vs. SS group) with each sample taken independently through Affymetrix® microarray hybridization. For GSEA, data for more than 23,000 genes were exported from Partek and analyzed with GSEA software (with 2852 gene sets encoded) to establish correlates with phenotypes of the gene sets.\r\nRESULTS: Distal colonic expression of 636 gene-sets were significantly upregulated in AA group samples (False Discovery Rates (FDR) values < 1 % and p value < 0.001; stringent statistical selection). These were validated by quantitative PCR of 14 selected genes across the immunological spectrum and over time-intervals of 3 days, 14 days and 28 days.\r\nCONCLUSIONS: Many key immunological, apoptosis-related and cellular function-associated gene-sets involved in the protective effect of AA in experimental colitis were identified. Further analysis of these profiles and biological pathways will assist utilizing these gene products and manipulating various aspects of these pathways to develop better therapeutic strategies in the management of intractable IBD.
GSE24218 ImmunoMouse Asthma 6 1 In order to determine if there are any genetic differences among lungs of Nogo-A/B knockout mice which may explain their enhanced asthmatic-like responses, we have employed whole genome microarray expression profiling as a discovery platform to identify any genes that may be altered in the lung of Nogo-A/B knockout mice. RNA was isolated from three biological replicates of mouse lungs from naive WT and Nogo-A/B Knockout mice and run on agilent array. Two genes was significantly altered in Nogo-A/B Knockout lungs, SPLUNC1 and RTN4 (Nogo) which was significantly decreased and confirmed by real-time PCR.
GSE24695 ImmunoMouse Influenza 9 2 Transcriptional response to virus infection in mice lacking type I and type III signaling\r\nThe transcriptional response to virus infection is thought to be predominantly induced by interferon (IFN) signaling. Here we demonstrate that, in the absence of IFN signaling, an IFN-like transcriptome is still maintained. This transcriptional activity is mediated from IFN-stimulated response elements (ISREs) that bind to both the IFN stimulated gene factor 3 (ISGF3) as well as to IFN response factor 7 (IRF7). Through a combination of both in vitro biochemistry and in vivo transcriptional profiling, we have dissected what constitutes IRF-specific, ISGF3-specific, or universal ISREs. Taken together, the data presented here suggests that IRF7 can induce an IFN-like transcriptome in the absence of type-I or -III signaling and therefore provides a level of redundancy to cells to ensure the induction of the antiviral state.
GSE25640 ImmunoMouse PulmonaryFibrosis 12 2 To study the possible fibrotic role of FIZZ2, bleomycin was used to induce pulmonary fibrosis in wild type and FIZZZ2 knockout mice, lungs were then harvested and processed for RNA isolation.\r\nWe used microarrays to detail the global gene expression regulated by FIZZ2 during fibrotic process.
GSE25778 ImmunoMouse Influenza 6 1 Pulmonary alveoli contain two distinct populations of epithelial cells. Type II cells produce pulmonary surfactant lipids and surfactant-associated proteins (SP) required for maintaining alveolar surface tension at the air-liquid interface and host defense against respiratory pathogens. Type II cells are also progenitors for epithelial type I cells, a terminally differentiated elongated cell that covers microvascular endothelial cells and participates in gas exchange. Despite some indirect evidence, it is unknown whether subpopulations of type II cells exist. We created a line of transgenic mice expressing enhanced green fluorescent protein (EGFP) under control of the human SP-C promoter. Expression of EGFP may define a subpopulation of type II cells because it is 1) expressed in approximately 10% of type II cells, 2) appears much later in embryonic development than SP-C, and 3) selectively proliferates in mice infected with influenza A virus. To determine whether EGFP defines a unique subpopulation of type II cells, RNA was isolated from EGFP-positive and negative type II cells and hybridized to affymetrix arrays. Of the genes detected in EGFP-positive cells, most were equally detected in EGFP-negative cells. However, approximately 350 genes were selectively elevated =5-fold in EGFP-positive cells and 1500 genes selectively expressed by EGFP-negative cells. These findings suggest EGFP defines a subpopulation of type II epithelial cells in this line of transgenic mice.
GSE25926 ImmunoMouse AD 15 3 The ß-amyloid precursor protein APP and the related APLPs, undergo complex proteolytic processing giving rise to several fragments. Whereas it is well established that Aß accumulation is a central trigger for Alzheimer disease (AD), the physiological role of APP family members and their diverse proteolytic products is still largely unknown. The secreted APPsa ectodomain has been shown to be involved in neuroprotection and synaptic plasticity. The ?-secretase generated APP intracellular domain AICD, functions as a transciptional regulator in heterologous reporter assays, although its role for endogenous gene regulation has remained controversial. To gain further insight into the molecular changes associated with knockout phenotypes and to elucidate the physiological functions of APP family members including their proposed role as transcriptional regulators we performed a DNA microarray transcriptome profiling of the frontal cortex of adult wild type, APP-/-, APLP2-/- and APPsa knockin (KI) mice, APPa/a, expressing solely the secreted APPsa ectodomain. Biological pathways affected by the lack of APP family members included regulation of neurogenesis, regulation of transcription and regulation of neuron projection development. Comparative analysis of transcriptome changes and qPCR validation identified co-regulated gene sets. Interestingly, these included heat shock proteins and plasticity related genes that were down-regulated in knock-out cortices. In contrast, we failed to detect significant differences in expression of previously proposed AICD target genes including Bace1, Kai1, Gsk3b, p53, Tip60 and Vglut2. Only Egfr was slightly up-regulated in APLP2-/- mice. Comparison of APP-/- and APPa/a with wild-type mice revealed a high proportion of co-regulated genes indicating an important role of the C-terminus for cellular signaling. Finally, comparison of APLP2-/- on different genetic backgrounds revealed that background related transcriptome changes may dominate over changes due to the knockout of a single gene. Shared transcriptome profiles corroborated closely related physiological functions of APP family members in the adult central nervous system. As expression of proposed AICD target genes was not altered in adult cortex, this may indicate that these genes are not affected by lack of APP under resting conditions or only in a small subset of cells.
GSE26070 ImmunoMouse ALS 8 1 Downregulation of expression and activity levels of the astroglial glutamate transporter EAAT2 is thought to be implicated in motor neuron excitotoxicity in amyotrophic lateral sclerosis (ALS). We previously reported that EAAT2 is cleaved by caspase-3 at the cytosolic C-terminus domain, impairing the transport activity and generating a proteolytic fragment found to be SUMO1 conjugated (CTE-SUMO1). We show here that this fragment accumulates in the nucleus of spinal cord astrocytes in vivo throughout the disease stages of the SOD1-G93A mouse model of ALS. In vitro expression in spinal cord astrocytes of the C-terminus peptide of EAAT2 (CTE), which was artificially fused to SUMO1 (CTE-SUMO1fus) to mimic the endogenous SUMOylation reaction, recapitulates the nuclear accumulation of the fragment seen in vivo and causes caspase-3 activation and axonal growth impairment in motor neuron-derived NSC-34 cells and primary motor neurons co-cultured with CTE-SUMO1fus-expressing spinal cord astrocytes. This indicates that CTE-SUMO1fus could trigger non-cell autonomous mechanisms of neurodegeneration. Prolonged nuclear accumulation of CTE-SUMO1fus in astrocytes leads to their degeneration, although the time frame of the cell-autonomous toxicity is longer than the one for the indirect toxic effect on motor neurons. As more evidence on the implication of SUMO substrates in neurodegenerative diseases emerges, our observations strongly suggest that the nuclear accumulation in spinal cord astrocytes of a SUMOylated proteolytic fragment of the astroglial glutamate transporter EAAT2 could take part to the pathogenesis of ALS and suggest a novel, unconventional role for EAAT2 in motor neuron degeneration in ALS.
GSE26476 ImmunoMouse Asthma 6 2 Selective stimulation of IL-4 receptor on smooth muscle induces airway hyper-responsiveness in mice.\r\nAbstract: Production of the cytokines IL-4 and IL-13 is increased in both human asthma and mouse asthma models and Stat6 activation by the common IL-4/IL-13R drives most mouse model pathophysiology, including airway hyperresponsiveness (AHR). However, the precise cellular mechanisms through which IL-4Ra induces AHR remain unclear. Overzealous bronchial smooth muscle constriction is thought to underlie AHR in human asthma, but the smooth muscle contribution to AHR has never been directly assessed. Furthermore, differences in mouse vs. human airway anatomy and observations that selective IL-13 stimulation of Stat6 in airway epithelium induces murine AHR raise questions about the importance of direct IL-4R effects on smooth muscle in murine asthma models and relevance of these models to human asthma. Using transgenic mice in which smooth muscle is the only cell type that expresses or fails to express IL-4Ra, we demonstrate that direct smooth muscle activation by IL-4, IL-13, or allergen is sufficient, but not necessary, to induce AHR and show that 5 genes known to promote smooth muscle migration, proliferation and contractility are activated by IL-13 in smooth muscle in vivo. These observations demonstrate that IL-4Ra promotes AHR through multiple mechanisms and provide a model for testing smooth muscle-directed asthma therapeutics.
GSE26600 ImmunoMouse AD 94 9 Methylazoxymethanol (MAM), the genotoxic metabolite of the cycad azoxyglucoside cycasin, induces genetic alterations in bacteria, yeast, plants, insects and mammalian cells, but adult nerve cells are thought to be unaffected. We show that the brains of young adult mice treated with a single systemic dose of MAM display DNA damage (O6-methylguanine lesions) that peaks at 48 hours and decline to near-normal levels at 7 days post-treatment. By contrast, at this time, MAM-treated mice lacking the gene encoding the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT), showed persistent O6-methylguanine DNA damage. The DNA damage was linked to cell-signaling pathways that are perturbed in cancer and neurodegenerative disease. These data are consistent with the established carcinogenic and developmental neurotoxic properties of MAM in rodents, and they support the proposal that cancer and neurodegeneration share common signal transduction pathways. They also strengthen the hypothesis that early life exposure to the MAM glucoside cycasin has an etiological association with a declining, prototypical neurodegenerative disease seen in Guam, Japan, and New Guinea populations that formerly used the neurotoxic cycad plant for medicine and/or food. Exposure to environmental genotoxins may have relevance to the etiology of related tauopathies, notably, Alzheimer’s disease, as well as cancer.
GSE26836 ImmunoMouse AD 12 2 Approximately 35 million people worldwide suffer from Alzheimer’s disease (AD). Existing therapeutics, while moderately effective, are currently unable to stem the widespread rise in AD prevalence. AD is associated with an increase in amyloid beta (A) oligomers and hyperphosphorylated tau, along with cognitive impairment and neurodegeneration. Several antidepressants have shown promise in improving cognition and alleviating oxidative stress in AD but have failed as long-term therapeutics. In this study, amitriptyline, an FDA-approved tricyclic antidepressant, was administered orally to aged and cognitively impaired transgenic AD mice (3xTgAD). After amitriptyline treatment, cognitive behavior testing demonstrated that there was a significant improvement in both long- and short-term memory retention. Amitriptyline treatment also caused a significant potentiation of non-toxic A monomer with a concomitant decrease in toxic oligomer A load, compared to vehicle-treated 3xTgAD controls. In addition, amitriptyline administration caused a significant increase in dentate gyrus neurogenesis as well as increases in expression of neurosynaptic marker proteins. Amitriptyline treatment resulted in increases in hippocampal brain-derived neurotrophic factor protein as well as increased tyrosine phosphorylation of its cognate receptor (TrkB). These results indicate that amitriptyline has significant beneficial actions in aged and damaged AD brains and that it shows promise as a tolerable novel therapeutic for the treatment of AD.
GSE27045 ImmunoMouse SLE 17 2 Renal infiltration with mononuclear cells is associated with poor prognosis in SLE. A renal macrophage/dendritic cell signature is associated with onset of nephritis in NZB/W mice and immune modulating therapies can reverse this signature and the associated renal damage despite ongoing immune complex deposition. Our findings suggest that mononuclear phagocytes with an aberrant activation profile contribute to tissue damage in lupus nephritis by mediating both local inflammation and excessive tissue remodeling.\r\nWe used microarrays to analyze the gene expression of renal isolated macrophages at early stage of lupus (young) during lupus nephritis (sick) and after induction of remission (Rem)
GSE27066 ImmunoMouse 2015Q2 36 5 Mouse lung samples from mice challenged with OVA or PBS control. Wildtype (B6) mice were tested, as well as mast cell deficient mice with engraftment of normal mast cells and mast cells deficient in IgE or Ifn-gamma signaling.
GSE27218 ImmunoMouse ALS 21 1 Cross-linking and immunoprecipitation coupled with high-throughput sequencing was used to identify binding sites within 6,304 genes as the brain RNA targets for TDP-43, an RNA binding protein which when mutated causes Amyotrophic Lateral Sclerosis (ALS). Use of massively parallel sequencing and splicing-sensitive junction arrays revealed that levels of 601 mRNAs are changed (including Fus/Tls, progranulin, and other transcripts encoding neurodegenerative disease-associated proteins) and 965 altered splicing events are detected (including in sortilin, the receptor for progranulin), following depletion of TDP-43 from adult brain with antisense oligonucleotides. RNAs whose levels are most depleted by reduction in TDP-43 are derived from genes with very long introns and which encode proteins involved in synaptic activity. Lastly, TDP-43 was found to auto-regulate its synthesis, in part by directly binding and enhancing splicing of an intron within the 3’ untranslated region of its own transcript, thereby triggering nonsense mediated RNA degradation.
GSE27302 ImmunoMouse IBD 16 3 Temporal geneome profiling of T cell transfer colitis model\r\nT cells critically regulate clinical inflammatory bowel diseases and T cell dependent experimental colitis models have gained prominent favor as useful models to identify potential pathogenic mechanisms. The naïve CD4+CD45Rbhigh cell transfer model into recombinase activating gene-1 deficient (RAG-/-) mice induces both colitis and small bowel inflammation reflecting Crohn's disease with unclear pathogenic mechanisms. Given the pathological similarities between the T cell transfer model of colitis and clinical disease, we sought to identify changes in whole genome expression profiles over time during the delelopment of colitis.
GSE27379 ImmunoMouse Influenza 6 0 Role for naturally occurring CD4+CD25+Foxp3+ regulatory T cells (nTregs) in counterbalancing this process. Using a transgenic murine model for autoimmune-mediated lung disease, we demonstrated that, despite pulmonary inflammation, lung-specific CD8+ T cells can reside quiescently in close proximity to self-antigen. Whereas self-reactive CD8+ T cells in the inflamed lung and lung-draining lymph nodes down-regulated the expression of effector molecules, those located in the spleen appeared to be partly antigen-experienced and displayed a memory-like phenotype. Since ex vivo-reisolated self-reactive CD8+ T cells were very well capable to respond to the antigen in vitro, we investigated a possible contribution of nTregs to the immune control over autoaggressive CD8+ T cells in the lung.
GSE27628 ImmunoMouse 2015Q2 34 6 Development of a suitable mouse model would facilitate the investigation of pathomechanisms underlying human psoriasis and would also assist in development of therapeutic treatments. However, while many psoriasis mouse models have been proposed, no single model recapitulates all features of the human disease, and standardized validation criteria for psoriasis mouse models have not been widely applied. In this study, whole-genome transcriptional profiling is used to compare gene expression patterns manifested by human psoriatic skin lesions with those that occur in five psor